Nuclear receptors in health and disease: signaling pathways, biological functions and pharmaceutical interventions.

Introduction

A cell’s ability to detect various extracellular signals depends on the chemical nature of the signaling ligands and the permeability of the plasma membrane to polar compounds, such as polypeptides. 1 , 2 This necessitates the production of two main types of signaling ligands and receptors. The first type, represented by growth factors, consists of polypeptides that generally cannot penetrate the cell membrane 3 – 5 ; therefore, their receptors must present sophisticated extracellular binding domains. The second type of nuclear receptor ligand includes small, relatively hydrophobic molecules such as steroid hormones, vitamins, fatty acid derivatives, dexamethasone and enzalutamide. 6 The hydrophobicity of these ligands allows them to pass through the cell membrane and reach the nucleus to bind to and activate nuclear DNA-binding proteins that then act as transcription factors. 7

Nuclear receptors (NRs) are a class of ligand-activated transcription factors that sense certain molecules, such as steroids, thyroid hormones and vitamins, to directly bind DNA and modulate gene expression, bypassing the need for cytoplasmic signal cascades that mediate surface receptor and nuclear transcription mechanisms. 8 – 10 They are essential for numerous physiological processes, including development, metabolism, reproduction, and homeostasis. To date, 48 NRs have been identified in the human genome, and 49 have been identified in mice. The typical structure of a nuclear receptor consists of a hinge region, a conserved ligand-binding domain and a DNA-binding domain, which are surrounded by various N- and C-terminal domains. 11 While some nuclear receptors are physically connected to chromatin, others remain in the cytoplasm until ligand interactions allow nuclear entry. These receptors bind to a DNA recognition sequence in or close to the promoters of the genes they control once they are attached to chromatin, either as homodimers or heterodimers. 12 , 13 These recognition sequences are commonly called hormone response elements (HREs) and are composed of two hexanucleotide sequences separated by a variable number of spacer sequences. 14 In addition, NRs can be indirectly recruited to the genome by tethering mechanisms by other DNA-bound transcription factors. 15 Several posttranslational modifications, such as phosphorylation, ubiquitination and SUMOylation, have been reported to modulate the activities of NRs. 16 – 19

The regulation of gene expression by nuclear receptors influences the proliferation, 20 differentiation 21 and death 22 , 23 of many different cell types, thereby playing important roles in the reproduction, development and physiology of metazoans. 24 – 27 The characterization of the NR superfamily marked a significant turning point in the field of endocrine physiology by establishing common molecular pathways governing the development and physiology of various animal species. The dysregulation of these genes can lead to cardiovascular disease, 28 cancer 29 and diabetes. 30 Research on NRs began in the mid-1980s when molecular cloning of several hormone receptors revealed their common structural framework. 31 As a consequence of their central role in governing cell fate, NRs constitute targets for 15–20% of all pharmacologic drugs. 32 , 33

Drugs that target specific NRs are frequently employed to treat a wide range of illnesses. Tamoxifen and raloxifene, for example, target the estrogen receptor (ER) and are used to treat osteoporosis and breast cancer. 34 , 35 Enzalutamide is used to treat prostate cancer by targeting the androgen receptor (AR), 36 , 37 whereas thiazolidinediones are used to treat type 2 diabetes by targeting peroxisome proliferator-activated receptor-gamma (PPARγ). 38 , 39 Compounds with stronger binding affinities and better specificity are currently under development as new NR-targeted drugs because the available drugs often lack specificity and exhibit significant side effects, including severe heart failure. 40 , 41 Thus, understanding the mechanism of NR gene selection and the development of specific inhibitors targeting NRs has become a pressing scientific issue in the field of biomedicine.

In this review, we systematically introduce NRs and their members, structure, functions and regulatory signals. We summarize recent findings regarding the function of NRs in regulating physiology and pathology and the relevance of these receptors to clinical drug development. Emphasis is given to research on the targeting of these receptors for disease management, the preclinical and clinical testing and development of novel drugs and the techniques and strategies that facilitate targeting and therapeutic efficacy.

Overview of nuclear receptors

The discovery of hormones dates back to the early 1900s 42 – 45 (Fig. 1 ). In 1905, Ernest Starling coined the term ‘hormone’. 44 , 45 In 1926, Tadeus Reichstein and Edward Calvin Kendall elucidated the structures of cortisone and thyroxine, 46 while Adolf Butenandt and Edward Adelbert Doisy first isolated estrogen in 1929. 47 , 48 became clear only after Elwood Jensen conducted a series of experiments in the late 1950s to determine how estrogen regulates reproductive organ maturation. 49 The rise of molecular biology in the 1980s led to groundbreaking advances, including the cloning of the human glucocorticoid receptor (GR) and the identification of the first estrogen receptor, ERα, from the ESR1 gene. 50 – 52 In 1985, Ronald Evans successfully cloned the human glucocorticoid receptor (GR), 50 , 51 while Pierre Chambon’s lab identified the first estrogen receptor, ERα, from the ESR1 gene. 52 They found that these receptors shared similarities with v-erbA, a viral oncogene recognized as a thyroid hormone receptor (TR) transcribed from the THRA gene. This discovery resulted in the placement of steroid and thyroid hormone receptors into a single grouping. A sequence comparison revealed a conserved evolutionary framework, highlighting structural and functional features that predicted the development of the nuclear receptor superfamily. Each receptor contains DNA-binding, ligand-binding, and transactivation domains. Soon after, receptors for other binding factors, such as retinoic acid and vitamin D, were cloned, confirming the existence of a receptor superfamily unified by structure. The formal establishment of the NR superfamily represented a major milestone, bolstering the hypothesis that the development and physiology of all animal species might be regulated by related molecular processes. Fig. 1 Historical timeline of nuclear receptor expression. Schematic timeline illustrating key milestones in the nuclear receptor research field. The timeline begins with the cloning of the first steroid hormone receptor cDNA and highlights significant advancements, culminating in recent discoveries enabled by “omics” technologies. Major breakthroughs and pivotal discoveries are annotated along the timeline

The therapeutic potential of NRs was recognized in the 1970s when it was shown that the estrogen blocker tamoxifen could inhibit ER-dependent breast cancer cells. 53 , 54 In prostate cancer, multiple nuclear receptors have been shown to inhibit tumor growth, proliferation, and metastasis, leading to significant interest in targeting these receptors as therapeutic strategies. 55 – 57 Dysfunction of NRs has been associated with specific diseases, such as infertility, obesity, and diabetes. 58 As key drug targets, NRs are crucial in studying the pathological mechanisms of metabolic diseases and related drug development. Today, they represent a huge family of pharmaceutically targetable proteins. This review discusses the current knowledge on NR-based therapeutic intervention in different types of disease.

Family members

The known sequence of the human genome revealed that forty-eight human NRs detect ligands, such as hormones, and translocate them into the nucleus to function as transcription factors regulating gene expression. 59 These receptors are classified into three main types on the basis of their ligand types or into eight subgroups on the basis of sequence homology. 11 , 60 Type I receptors are steroid receptors, including the ER, AR, progesterone receptor (PR), mineralocorticoid receptor (MR) and GR. 61 , 62 Their ligands are steroid hormones such as sex hormones, glucocorticoids and mineralocorticoids. 63 Type II receptors are nonsteroid receptors, such as thyroid hormones (TRα and TRβ), retinoic acid receptors (RARα, β), vitamin D receptors (VDRs) and peroxisome proliferator-activated receptors (PPARα, β and γ). 64 Type III receptors include orphan receptors whose endogenous ligands are unknown or that do not bind to any ligands, such as the testicular receptor and germ cell nuclear factor. 65 Alternatively, NRs can be divided into eight subgroups that are similar to classical receptors but differ enough individually, named thyroid hormone receptor-like family, retinoid X receptor-like family, estrogen receptor like family, nerve growth factor IB-like family, steroidogenic factor-like family, germ cell nuclear factor-like family, and those with two DNA-binding domains, as well as recently identified typically structured NR (CgNR8A1) in metazoans such as mollusks, annelids, cnidarians, echinoderms and hemichordates. 66 , 67

Structure

Except for the dose-sensitive sex reversal-adrenal hypoplasia congenital critical region on the X chromosome, gene 1 (DAX1) and the small heterodimer partner (SHP), all NRs are typically single-chain polypeptides that share four or five functional domains , 68 including the N-terminal transcription activation domain (NTD), the DNA-binding domain (DBD), the ligand-binding domain (LBD), the C-terminal transcription activation domain (CTD) and a hinge domain (H) that connects the DBD and LBD (Fig. 2 ). Fig. 2 Diagram of the structural model of nuclear receptors. Nuclear receptors share four functional domains: the N-terminal transcription activation domain (NTD), the DNA binding domain (DBD), the ligand binding domain (LBD), and a hinge domain (H) that connects the DBD and LBD. Some NRs also contain a highly variable C-terminal transcription activation domain (CTD)

The NTD, which is located at the N-terminus and comprises 25–603 amino acids (AAs), contains the first of two transactivation regions (AF-1) and possesses transcriptional activator functions. 69 , 70 The A/B domain is intrinsically disordered, which makes obtaining full-length 3D representations of the receptor difficult. 71 , 72 The second identified subunit is the DBD, with 66--68 AAs, including two zinc fingers, which are typically obscured because of lower DNA affinity when the hormone is absent. 73 – 75 Once a hormone is bound, the zinc fingers dock the hormone–receptor complex to hexanucleotide response elements located within NR-regulated promoters that determine the receptor’s regulatory specificity. The DBD also serves as an intermolecular interaction site for receptor dimerization. 76 The LBD is located at the receptor’s C-terminus and contains 220--250 AAs. 77 The LBD binds to the cognate hormone or ligand through an interior binding pocket. 78 , 79 It also has an AF-2 site for recruiting various coactivating proteins, such as heat shock proteins (HSPs), to facilitate interactions with chromatin-remodeling proteins and the transactivation domain. 80 – 82 The LBD plays a crucial role in mediating self-assembly reactions, such as dimerization or tetramerization, which are essential for high-affinity binding to DNA response elements. 83 The DBD is connected to the LBD via a flexible domain, the ‘hinge’, which is related primarily to the nuclear localization signal of NRs and may influence the intracellular trafficking and subcellular distribution of the hormone‒receptor complex. 84 , 85 The hinge region also contains a short NLS, and its phosphorylation is coupled to elevated transactivation. 86 , 87

However, not all NRs have all four typical domains. Members of the NR0 subfamily, for example, frequently have neither a DBD nor an LBD in their structures. 88 Among these, NRs with only the LBD and no DBD, such as Dax-1 and SHP, are nonetheless capable of binding to other transcription factors (TFs) and suppressing the expression of genes downstream. Finally, some NRs also possess a short, highly variable C-terminal domain (CTD or F domain) that often has unknown functions. 89 , 90 However, current research has revealed a critical function of the F domain in the ERα reaction to select ER modulators (SERMs), particularly in SERM-mediated LBD dimerization and AF-1 activity. 91

Origins and evolution

NRs were thought to have evolved approximately 600 million years ago in the common ancestor of bilaterian animals, enabling them to sense and respond to internal and external signals. 92 This evolution likely involved genetic amplification and mutation, contributing to the functional diversity of the NR superfamily. 93 Most NR ligands are small, hydrophobic molecules that pass through cell membranes, although some, such as thyroid hormones, are actively transported into cells. 94 While NRs were initially termed ligand-binding proteins, it remains debated whether their common ancestor bound ligands or functioned as constitutively active receptors. Over 50% of NRs are orphan receptors lacking known ligands, although some have been shown to bind metabolites, suggesting a role in sensing metabolic changes. 95 , 96 The evolution of the LBD enabled interactions with small molecules and coregulators, increasing NR versatility. 97 Gene duplication during early metazoan evolution expanded and specialized the NR superfamily into subfamilies such as steroid hormone receptors, thyroid hormone receptors, and orphan receptors. The coevolution of NRs and their ligands increases their physiological complexity. For example, vertebrate NRs, such as glucocorticoid and estrogen receptors, have evolved high specificity for steroid hormones, which are crucial for the stress response and reproduction. 98

In 1992, a comparison of the DNA-binding domains of known NRs led to the construction of a phylogenetic tree, suggesting a common ancestor. 99 By 1997, an alternative hypothesis emerged, suggesting that the original NR was an orphan receptor that gradually gained ligand-binding ability. 100 The earliest NRs are believed to have evolved as orphan receptors that lack defined ligands and are involved in regulating fundamental processes such as metabolism and cellular signaling. 101 Over time, orphan receptors adapt to regulate broader metabolic pathways, including lipid homeostasis and detoxification. A recent discovery of the NR7 subfamily has filled a critical gap in the understanding of the evolution of NR dimerization capabilities. Phylogenetically situated between class I NRs (monomers or homodimers) and class II NRs (heterodimers), the NR7 subfamily acts as a “missing link” in the transition from homodimerizing to heterodimerizing nuclear receptors. 102

Mechanisms of action

Nuclear receptors can modulate gene expression through direct binding to target genes as well as through interactions with other NRs. 103 , 104 The interplay between NR actions can be described at progressively more detailed levels, with various regulatory modes involved in upstream events that influence downstream gene transcription and crosstalk events at the DNA level that directly influence gene transcription. 105 The existence or lack of physical connections between the relevant NRs could further alter the crosstalk mechanisms at the DNA level.

Crosstalk between nuclear signalings

Nuclear receptors can share overlapping arrays of target genes or regulate distinct genes that are part of the same downstream activity or pathway (Fig. 3 ). There is a wealth of experimental evidence to support endpoint modifications in gene expression that occur after NR crosstalk. The relationship between ERα and the PR was among the first observed examples of crosstalk between nuclear receptors. 106 Estradiol-stimulated ERα activity was found to be suppressed by liganded PR isoforms, and the ligand, promoter and cell type were demonstrated to influence this suppressive crosstalk. 106 , 107 Interactions between GRα and PPARα are critical in regulating shared subsets of target genes and different stages of signal transduction cascades involved in inflammatory and metabolic pathways. 108 , 109 For example, both GRα and PPARγ have been shown to repress genes associated with TLR4- and TLR9-induced innate immune responses in primary peritoneal macrophages. 110 , 111 However, there are significant differences in how these NRs achieve gene repression, which involves distinct transcriptional corepressor complexes. These variations in regulatory mechanisms highlight the complexity and specificity of gene regulation mediated by GRα and PPARγ in immune and metabolic contexts. Fig. 3 Crosstalk modes of NR signaling. Various regulatory modes involved in NR signaling influence downstream gene transcription. For example, different types of nuclear receptor signaling can simultaneously regulate the expression of the same gene (Modes 1, 3 and 4) or regulate different genes belonging to the same pathway (Mode 2). Different nuclear receptors may share the same target genes (Mode 5). In addition, crosstalk between two NRs can influence each other’s gene or protein expression (Mode 6)

More complex types of crosstalk, such as reciprocal or unidirectional regulation of the expression of NR genes or proteins and ligand availability, can sometimes occur. 112 , 113 For example, glucocorticoid-activated GRα was reported to upregulate PPARα mRNA expression. 109 , 114 Conversely, fenofibrate-activated PPARα was shown to downregulate GRα expression at the posttranscriptional level in a time- and dose-dependent manner. 115 , 116 In rodent adipocytes, antidiabetic PPARγ ligands increase the expression of PEPCK-C mRNA, which encodes the key glyceroneogenic enzyme EC4.1.1.32. 117 In contrast, dexamethasone-activated GRα counteracted this induction at the transcriptional level. These results show that the processes involved in NR crosstalk are not unique; different pairs of nuclear receptors can interact through distinct crosstalk mechanisms according to the stimulus, expression level, cell type, pathway and genes involved. It is probable that many other modes of crosstalk will be uncovered as our knowledge expands to include other intracellular organelles and the shuttling of NRs.

Crosstalk between nuclear receptors at the DNA level

At the DNA level, NR crosstalk can take two primary forms 13 , 118 (Fig. 4 ). In one scenario, NRs physically interact to regulate specific target genes (direct crosstalk). In another context, NRs do not actually connect but still engage in unidirectional or bidirectional interactions (indirect crosstalk). When two nuclear receptors interact directly, they can bind to DNA sequences that are either closely positioned or farther apart. Alternatively, they can bind DNA sequences through the action of other transcription factors. A well-known example of this is the peroxisome proliferator-activated receptor PPARs, which are of three types: PPARα, PPARβ/δ and PPARγ. Most of these proteins are heterodimers connected to retinoid X receptors (RXRs) that regulate gene transcription, 119 , 120 but they can also be fine-tuned by pairing with a different ligand. Multiple coactivators can interact with heterodimer complexes to supplement and stabilize their activity in regulating lipid metabolism, adipogenesis and inflammation. 121 , 122 Further instances of direct NR connections have been reported for steroid receptors. GRα and AR have many target genes in common due to the recognition of partial palindromic repeats of the sequence 5′-TGTTCT-3′. 123 GRα–AR heterodimerization has been proposed as the mechanism underlying the mutual inhibition of the transcriptional activities of these two receptors, allowing for differential regulation of specific genes. 124 , 125 Furthermore, AR and GR share significant similarities in the dimerization structure of their LBDs, which sheds new light on the previously reported structure of the GR LBD. 126 The mechanisms of direct crosstalk may allow for dual NR ligand control, but the exact conditions for this process have not been determined. Context-specific influences, such as tissue or cell type and differentiation status, are likely to lead to different interaction patterns, resulting in varied biological responses. 127 , 128 Fig. 4 Crosstalk modes at the DNA level. At the DNA level, nuclear receptors engage in crosstalk by indirectly or directly interacting with DNA. Part a outlines indirect regulation modes, where no physical interaction occurs, whereas Part b describes regulatory mechanisms involving direct physical interactions among nuclear receptors (NRs). Indirect regulation modes include: NR signaling pathways may compete for overlapping DNA-binding sites; NR heterodimer partners may cause redistribution or squelching; Components of the transcriptional machinery, such as RNA polymerase II (Pol II) and transcriptional coregulators, may cause redistribution or squelching; The alteration of shared coregulators can influence the activity of other NRs. One NR family member can act as a pioneering factor to facilitate chromatin loosening and enable the subsequent binding of other NRs. Direct physical interactions includes: Paired receptors may cooperate for direct DNA binding or through DNA looping; Direct crosstalk can occur with just one partner contacting the DNA; Two nuclear receptors engage in crosstalk through protein-protein interactions with other transcription factors (TFs); The sequestration of one or both NRs (originating from other modes, (f–i) away from the DNA due to heterodimer interactions

In the absence of an actual connection, NR signaling pathways can indirectly influence crosstalk through several mechanisms. 129 – 131 They may compete for overlapping DNA-binding sites by redistributing shared proteins or parts of the transcriptional machinery, such as RNA polymerase II or transcriptional coregulators; by regulating the expression of shared coregulators; and by acting as pioneering factors that loosen chromatin to facilitate the binding of additional NRs. For example, peroxisome proliferator-activated receptor alpha (PPARα) binds to estrogen-related receptor (ERR) target genes in heart tissue through ERR response element motifs via a histone deacetylase SIRT1-dependent mechanism. 132 RXR, the PPAR partner, can trigger PPAR-independent activities on PPAR response element (RE)-controlled genes via RXR homodimerization, adding another layer of control to an intricate metabolic pathway. 133 Members of the PPAR and ERR subfamilies can be further connected through shared coregulators, including PGC1α and PGC1β, as well as through common regulators such as low-energy-sensing AMP kinase. 134 , 135 For example, during adipocyte differentiation and osteoclastogenesis, PGC1β, a coregulator that is upregulated by ERRα, can be recruited by PPARγ and other transcriptional regulators to enhance their adipogenic properties. 136 Reduced PGC1β expression levels due to downregulation of ERRα resulted in decreased transcriptional activity of PPARγ. These reports provide evidence for the existence of complex combinations of indirect regulatory modes.

Genomic and nongenomic mechanisms

The function of nuclear receptors can be achieved via genomic or nongenomic pathways (Fig. 5 ). Genomic mechanisms involve the direct regulation of gene expression through binding to DNA. This mechanism usually plays a critical role in long-term physiological processes, such as development, metabolism, and homeostasis. Nongenomic mechanisms involve rapid, transcription-independent actions of nuclear receptors. These processes occur within minutes and are crucial for swift cellular responses, such as ion channel modulation, cell migration, and acute stress responses. Fig. 5 Nuclear receptors precisely regulate cell fate and metabolic processes. Nuclear receptors play crucial roles in regulating cell fate by influencing various cellular processes, including proliferation, differentiation, senescence and apoptosis, by acting as transcription factors. Additionally, members of the nuclear receptor family control the synthesis rates of different metabolic enzymes across various tissues, affecting processes such as glucose, lipid and bile acid metabolism, as well as adipocyte differentiation and plasma lipoprotein modulation. By regulating the balance between the storage, utilization and production of these macromolecules, nuclear receptors ensure metabolic flexibility, enabling the organism to adapt to fluctuations in energy availability and demand

Genomic mechanisms

Prior to binding to the specific DNA sequences of target genes known as hormone HREs to control transcription, NRs are typically in an inactive state and require activation through the binding of a cognate ligand. 15 , 137 With many receptors, in the absence of ligands, molecular chaperone proteins such as heat shock protein 90 (HSP90) and HSP70 anchor them in the cytoplasm in an inactive state. 138 Upon ligand binding, the NR undergoes a conformational shift that causes it to separate from the heat shock protein and become active. 139 This allows the hormone–receptor complex to translocate into the cell nucleus after its nuclear localization sequence (NLS) has been revealed. 140 , 141 Once inside, the complex binds to a specific sequence in the target gene known as an HRE to regulate its transcription. In addition to detaching the HSPs, ligand binding can promote receptor phosphorylation, which further enhances the ability of the receptor to bind to HREs. 142 In general, NRs undergo a change from a non-DNA-binding form to a DNA-binding form upon activation, but some types, such as thyroid hormone receptors, retinoic acid receptors and retinoid X receptors, are retained in the nucleus regardless of their ligand binding status. 143 They are already bound to HREs but complex with corepressor proteins, which makes them transcriptionally inactive. 144 , 145 However, upon receiving ligand activation signals, the corepressor dissociates, and coactivator proteins are recruited. The NR/DNA complex then enlists more proteins, such as RNA polymerase, to aid in the transcription of DNA into mRNA. 146 – 148

Nuclear receptors can directly bind DNA via three different modes, namely, homodimers, heterodimers, or monomers, depending on the type of NR. 13 For example, glucocorticoid receptors (GRs) bind to HREs after forming homodimers. 149 , 150 In contrast, retinoic acid receptor-related orphan receptor gamma (RORγ) binds as a monomer to the DNA response region to control gene transcription and expression. 151 , 152 The retinoid X receptor (RXR) can either bind to itself as a homodimer or pair with other nuclear receptors as a heterodimer to activate downstream gene transcription. 153 – 155 To make this process even more complicated, some NRs can form nonclassical heterodimers, which are only activated by outside ligands. Thus, unanticipated adverse effects could appear when developing therapeutics because NRs can operate through nonclassical routes. 156 – 159

The identification of coregulatory proteins that interact with and control the transcriptional action of NRs in the mid-1990s was another pivotal development in our knowledge of the mechanism of action of NRs. 160 , 161 These coregulators have a variety of functions, such as chromatin remodeling, which modifies the target gene’s transcriptional accessibility, or bridging, which maintains the binding of other coregulatory proteins. 162 The intrinsic histone acetyltransferase (HAT) activity of coactivator proteins can promote gene transcription by reducing the affinity of histones for DNA. 163 On the other hand, the recruitment of histone deacetylases (HDACs) by corepressor proteins increases the number of bonds between histones and DNA and suppresses gene transcription. 164 These coactivators or corepressors enable nuclear receptors to function as inducible scaffolds that coordinate large transcriptional complexes, allowing different ligands to induce distinct receptor conformations. 163 , 165 These changes could expose specific protein–protein interaction surfaces, making them available for coregulator binding. This hypothesis provides an explanation for how structurally different ligands, such as selective estrogen receptor modulators, could influence multiple genes in the same cell via the same receptor or how they could jointly regulate the expression of a single gene. Depending on the tissue-specific location of coregulators, the same ligand can also control specific genes in different tissues or at different developmental stages. 166 , 167 Nuclear receptor/coregulator complexes that alter chromatin shape and DNA accessibility are produced by receptor-bound coregulators, which can also directly interact with the core RNA polymerase through their enzyme action. In addition, there is no set link between two distinct nuclear receptors, as they can change depending on the target genes and tissues that are engaged. Transcriptional regulation by NRs can be affected by epigenetic variables such as chromatin remodeling, DNA methylation and histone modification. 168 , 169

Nongenomic mechanisms

In addition to acting as transcription factors in the nucleus to regulate target gene expression (genomic function), NRs can also operate through a molecular mechanism independent of transcriptional activity (nongenomic function) 170 – 172 (Fig. 5 , Fig. 6 ). This nongenomic role requires NRs to be localized to specific subcellular structures, 173 – 175 where they directly interact with various intracellular proteins to rapidly regulate cellular stress responses and signal transduction pathways. Their subcellular translocation can occur either by alternative splicing or posttranslational modifications through free shuttling or with the assistance of other proteins. 176 , 177 As an example, the plasma membrane is home to a truncated variant of the thyroid hormone receptor. This localization enables them to participate in several biological processes, including the endoplasmic reticulum stress response, apoptosis, autophagy, fatty acid oxidation within mitochondria and the regulation of centrosome homeostasis and cell mitosis. Nongenomic NR signaling frequently involves phosphorylation cascades mediated through pathways associated with AMPK, cAMP/PKA, PI3K/AKT, and Hippo/Yap and signaling via Wnt/β-catenin and MAPK. 178 – 183 Fig. 6 Platelets are good models for investigating the possible nongenomic impacts of nuclear receptors. Because of their anucleate origin, well-characterized mechanisms, and quick reactions, platelets offer a model system for examining any non-genomic impacts of the NRs. Non-genomic roles of NRs include controlling intracellular calcium levels, ion channel function, kinase and phosphatase activity, and second messenger synthesis. It has been discovered that human platelets contain a number of NRs, and that certain NR agonists have anti-platelet actions through a range of mechanisms

Several NRs have been found to propagate rapid nongenomic effects for cellular protection in addition to their defined genomic effects. Their nongenomic functions operate through the control of kinase/phosphatase activity, 184 , 185 intracellular calcium levels, 186 , 187 ion channel function 188 , 189 and the production of second messengers. 190 Accumulating data indicate that RXRα also possesses extranuclear nongenomic functions. Previous studies have demonstrated that RXRα engages in some nongenomic activities through the creation of heterodimers with Nur77. 191 In response to specific apoptotic stimuli, RXRα-Nur77 heterodimers are translocated from the nucleus to the mitochondria, where they regulate apoptosis. 192 Recent research has shown that truncated RXRα (tRXRα) has an important function in the PI3K/AKT signaling pathway, where it interacts with the p85α subunit to increase AKT activation and promote cell proliferation both in vitro and in vivo. 193 , 194 Notably, glucocorticoids (GCs) manifested nearly instantaneous nongenomic effects through nonspecific interactions with cell membranes and targeted interactions with cytosolic GRs (cGRs) or membrane-bound GRs (mGRs). 124 , 195 , 196 This rapid nongenomic action of GCs could also contribute to their anti-inflammatory effects through prolonged genomic processes, particularly in managing inflammatory diseases (Fig. 6 ). 197 , 198 For example, recent studies revealed that GCs quickly enhanced the effects of bronchodilators used to treat allergic asthma. 199 Other NRs, including PPARα, LXR and FXR, have also been reported to perform nongenomic functions. 189 , 191 , 200 The possibility of turning NR ligands into effective medicines should be explored through the characterization of these extragenomic processes and the discovery of new binding partners and pathways in addition to their known genomic effects.

Platelets are useful models for investigating the potential nongenomic effects of NRs because they lack nuclei and possess well-characterized reactions. 189 , 201 ERβ, but not ERα, is known to be expressed on human platelets and to affect their function. 202 In addition, some studies have shown that platelets isolated from male rats exhibit a stronger aggregation response than those from female rats do, likely due to an increase in androgenic steroids. 203 , 204 This conclusion was supported by findings that castration reduced platelet aggregation in male rats, 205 an effect that was reversed with testosterone treatment. 206 LXR and FXR ligands negatively regulate platelet function by inhibiting platelet signaling and the formation of procoagulant-coated platelets. 207 – 210 For example, LXR ligands induce a procoagulant state in platelets, which is marked by the exposure of phosphatidylserine and α-granule contents on the surface of the platelet, coupled with mitochondrial membrane depolarization, reduced calcium mobilization and decreased affinity of integrin αIIbβ3, which ultimately inhibits platelet aggregation. 209 , 211 Similarly, FXR ligands can cause platelet swelling and transformation into procoagulant-coated platelets, a process dependent on cyclophilin D activity. 212 FXR ligands also increased cGMP levels, which increased PKG activity and VASP S239 phosphorylation, further suppressing platelet activation. 189 Other studies have identified PPARα as a key mediator of the antiplatelet effects of statins and fenofibrate. 213 Treating platelets with PPARα ligands, such as fenofibrate or statins (e.g., simvastatin), inhibited ADP-stimulated platelet activation by increasing intracellular cAMP levels through a PPARα-dependent mechanism. 214 This role of PPARα was further confirmed by experiments showing that fenofibrate-induced inhibition of platelet activation and prolonged bleeding time were absent in PPARα-deficient mice 215 ; the reversion of this inhibitory effect by the PPARα antagonist GW6471 further highlighted its dependence on PPARα.

Subsequent studies revealed the unexpected presence of retinoic acid receptors (RARs) in the cytosol of Sertoli cells, hepatic stellate cells and neurons. 216 – 218 In Sertoli cells, RARα was found to be a substrate for small ubiquitin-like modifier-2 (SUMO-2), and its cytosolic or nuclear localization was influenced by a dynamic process of sumoylation and desumoylation. 219 , 220 Additionally, in Sertoli and hepatic stellate cells, RARα is retained in the cytosol through interactions with the cytoplasmic adaptor for RAR and TR (CART1) protein or with cytoskeletal proteins that sequester the receptor outside the nucleus. 144 Furthermore, in hippocampal neurons, independent studies have shown that RARα is exported to dendritic RNA granules, where it is associated with a specific subset of mRNAs and RNA-binding proteins. 221 – 223 Interestingly, in response to retinoic acid (RA), this extranuclear pool of RARα rapidly initiates the local translation of the postsynaptic glutamate receptor GluR1, leading to an increase in synaptic strength. 224 , 225 In light of this growing body of knowledge, understanding these nongenomic mechanisms can lead to the development of new therapeutic strategies that exploit the rapid and diverse roles of nuclear receptors outside of their traditional genomic functions. By targeting the nongenomic pathways of nuclear receptors, it may be possible to create drugs with faster onset times and more specific effects, thereby increasing the efficacy of treatments for various diseases.

Functions in physiology and pathology

Nuclear receptors are of key importance in physiology and pathology because they regulate multiple cellular functions (Fig. 5 ). For example, NHR-6, the only NR4A-type nuclear receptor in the roundworm Caenorhabditis elegans , has been implicated in the development of the nervous system. 226 During development, the nervous system produces highly specialized neurons with distinct functional characteristics. A prime example is the C. elegans BAG chemosensory neurons. 227 Under certain circumstances, BAG neurons sense the concentration of carbon dioxide in respiratory gas and translate it into reactions of attraction or repulsion; ETS-5 and its target gene NHR-6 are essential for this process. 228 In contrast to ETS-5, which is engaged in both the attraction and avoidance of carbon dioxide, NHR-6 is an NR that is exclusively involved in the attraction process. 229 These findings imply that gene regulatory mechanisms supported by NR subtypes have undergone evolutionary conservation. NHR-6 is necessary for BAGs to exhibit exceptional capacity to adaptively assign positive or negative valences to chemosensory stimuli, and it is a key modulator of the functional plasticity of the neural system. 226 It is clear that NRs are of the greatest importance for the proper functioning of numerous processes in cellular lipid metabolism, 230 , 231 energy homeostasis 232 and the inflammatory response 233 ; cell proliferation and differentiation are critically dependent on nuclear receptors.

Pathological changes in nuclear receptors, such as mutations, altered expression levels, or dysregulated activity, are linked to a wide range of diseases, including cancer, metabolic disorders, inflammation, and cardiovascular conditions. For example, the overexpression of ER in breast cancer drives tumor growth, 234 whereas aberrant AR can cause therapy resistance in prostate cancer. 235 Impaired PPAR function is associated with metabolic disorders such as obesity and type 2 diabetes, 236 whereas dysregulated liver X receptors (LXRs) disrupt cholesterol homeostasis, exacerbating cardiovascular disease. 237 Aberrant GR activity exacerbates inflammatory conditions and may induce corticosteroid resistance. Altered retinoid X receptor (RXR) function has been linked to neurodegenerative diseases such as Alzheimer’s disease. These pathological changes not only hold diagnostic and prognostic value but also serve as therapeutic targets. For example, ER, PR, and HER2 expression levels guide breast cancer classification and treatment, with SERMs such as tamoxifen proving effective in ER-positive patients. AR inhibitors are crucial in prostate cancer, where AR expression levels and mutations influence therapeutic outcomes. Additionally, radiolabeled ligands such as [F-18]-estradiol enable imaging of ER-positive tumors via PET scans, 238 aiding in diagnosis and treatment monitoring. In summary, nuclear receptor alterations play a dual role in clinical practice as both therapeutic targets and biomarkers, underscoring their critical contribution to precision medicine and improved patient outcomes.

Cell fate

Nuclear receptors are essential for regulating cell fate through their function as transcription factors with effects on proliferation, 239 differentiation, 240 senescence 241 and apoptosis. 242 Through nongenomic mechanisms, NRs modulate signaling pathways that determine whether a cell will continue to divide, differentiate into a specific cell type, or undergo programmed cell death. 243

The ER has been the most studied ER, mainly because of the estrogen dependence of the growth of certain breast cancer cells. The function of estrogen receptor alpha (ERα/ER) defines the most common type of breast cancer. 244 , 245 Numerous associated elements that function as regulators of estrogen-driven transcriptional pathways have been discovered, indicating that the ER cannot function solely by itself. 246 Enhancer sequences are cis-regulatory ER binding sites that are located mainly away from transcriptional start sites, according to genome-wide profiling of chromatin binding. 247 There is growing evidence that global enhancer activation is involved in tumor aneuploidy and carcinogenesis. 248 Short DNA enhancer elements are crucial for maintaining a coordinated gene expression program specific to cell types during development and differentiation. 249 Other nuclear receptor ligands, such as all-trans retinoic acid (atRA) and 1,25(OH)2D3, induce cell differentiation. 250 – 252 RA, the primary bioactive metabolite of retinol (vit A), has a range of pleiotropic effects on cell growth and differentiation, which are important in adult physiology and embryonic development. 253 Members of the NR class of transactivators, specifically the retinoic acid receptors RARα, RARβ and RARγ, are the main mediators of activity. 254 For example, prostate cancer-induced bone formation is decreased, and the endothelial-to-osteoblast transition (EC-to-OSB) is inhibited when the retinoic acid receptor (RAR) is activated. 255 , 256 Treatment with the RARγ agonist palovarotene, which has been tested for heterotopic ossification in fibrodysplasia ossificans progressiva , inhibited osteoblast mineralization and the EC-to-OSB transition in vitro. It also reduces the growth and formation of tumor-induced bone in several models of osteogenic prostate cancer. 255 Compared with mature hepatocytes, hepatocytes induced in a 3D environment exhibited lower activity of the nuclear receptor THRB. The addition of THRB ligands during differentiation upregulated not only the expression of CYP3A4 but also the expression of multiple hepatocyte-related genes and increased histone acetylation; the induced differentiated hepatocytes were more similar to mature hepatocytes. 21 In addition, the nuclear receptor Nur77 regulates the expression of genes involved in fatty acid absorption and transport, thereby blocking the uptake of exogenous fatty acids by cells and inhibiting the signaling pathways that promote breast cancer cell proliferation. 27 These findings highlight the significant role of NRs in controlling cell growth and differentiation.

NRs have also been shown to be involved in cellular senescence and cell death processes. Three members of the NR4A1/Nur77/NGFIB orphan nuclear hormone receptor subfamily (NR4A1, NR4A2 and NR4A3) have been the most studied. NR4A2 was reported to maintain anchorage-independent growth, thereby reducing cell death, known as anoikis, in HeLa cells. 257 Following acute kidney injury (AKI), Nur77 and its family members Nurr1 and Nor-1 stimulate epithelial apoptosis. A conformational shift in Bcl2 and an increase in proapoptotic Bcl-xS protein levels are involved in Nur77-mediated kidney damage. 258 Furthermore, YAP controls the transcription, phosphorylation and mitochondrial localization of NR4A1 to mediate the proapoptotic and antitumor actions of the Hippo pathway. In turn, NR4A1 acts as a feedback inhibitor of YAP, leading to its destruction, which prevents YAP from participating in carcinogenesis and liver regeneration. 259 In addition, Nur77 interacts with DNMT3b, increasing GLS1 promoter methylation and decreasing GLS1 expression and glutaminolysis, which leads to the induction of HSC senescence. 260 Hepatocyte nuclear factor 4α (HNF4α, NR2A1), another strongly conserved NR superfamily member, suppresses prostate tumorigenesis by arresting the cell cycle at the G2/M phase and p21-driven cell senescence. 261 NR subfamily 1 group I member 2 (NR1I2), also called PXR (pregnane-X receptor) or PAR (pregnane-activated receptor), has been implicated in blunting the expression of the proapoptotic genes TP53 and BAK1 (BCL2 antagonist/killer 1) to prevent apoptosis from toxic bile acids. 262 The retinoid RXRα has been shown to suppress the production of ITPR2 and control calcium signaling via ITPR2 and the mitochondrial calcium uniporter (MCU). After reducing the degree of DNA damage, the overexpression of RXRα delays replicative senescence. 263 ZBTB17, a zinc finger protein, was shown in another study to interact with RXRα. Notably, ZBTB17 knockdown initiates a series of events, including DNA damage, decreased mitochondrial membrane potential (MMP), RXRα-dependent intracellular calcium signaling and cellular senescence. 264 Under metabolic and genotoxic stresses, LXR/CD38 activation promoted lysosomal cholesterol efflux and nicotinamide adenine dinucleotide (NAD + ) depletion in macrophages, which caused cholesterol-induced macrophage senescence and neurodegeneration. 265

Cellular metabolism

Members of the NR family control the pace at which different metabolic enzymes are synthesized in different tissues, 266 which affects processes including the metabolism of glucose, lipids and bile acids; adipocyte differentiation; and plasma lipoprotein modulation. 267 , 268 By influencing the balance between the storage, utilization and production of these macromolecules, NRs ensure metabolic flexibility, allowing the organism to adapt to fluctuations in energy availability and demand (Fig. 7 ). Their regulatory functions are particularly critical during periods of fasting, stress, or increased physical activity, where their precise control is essential for maintaining overall metabolic health. Fig. 7 Examples of nuclear receptors involved in regulating metabolic pathways. Cellular metabolic pathways provide the energy and materials essential for cell survival. Nuclear receptors transcriptionally regulate genes that encode nutrient transporters and metabolic enzymes involved in these processes. The pathways include the following: 1. Glycolysis, 2. Pentose phosphate pathway (PPP), 3. Gluconeogenesis, 4. Lactate oxidation, 5. Autophagy, 6. Amino acid catabolism, 7. Redox homeostasis, 8. Mitochondrial biogenesis/dynamics, 9. Oxidative phosphorylation (OXPHOS), 10. Tricarboxylic acid (TCA) cycle, 11. Ketogenesis/ketolysis, 12. Glutaminolysis, 13. Ca 2+ homeostasis, 14. Fatty acid oxidation (FAO), 15. Lipolysis

Glucose metabolism and gluconeogenesis

Glucose is the primary metabolic fuel for mammals and plays a crucial role in maintaining energy homeostasis. 269 , 270 During the fed state, circulating glucose originates primarily from the absorption of nutrients in the intestines. 271 However, under fasting or energy-demanding conditions, the body relies on two additional sources to maintain glucose levels: the breakdown of stored glycogen through glycogenolysis and the production of new glucose molecules via gluconeogenesis. 272 – 274 These complex metabolic processes are intricately regulated, and NRs play a key role in coordinating them. As molecular sensors, NRs detect changes in the body’s energy status and modulate the expression of genes involved in glucose metabolism. 275 , 276 The activation of PXR by its ligand, pregnenolone-16α-carbonitrile (PCN), impaired glucose tolerance by dysregulating glucose transporter 2 (GLUT2) function through two distinct mechanisms. 277 First, it reduced the expression of GLUT2 in both mouse liver and wild-type hepatocytes. Second, it triggers the transport of GLUT2 from the plasma membrane to the cytosol in the liver, thereby suppressing glucose uptake in primary hepatocytes. Additionally, data mining of published chromatin immunoprecipitation/sequencing results revealed that the Glut2 gene is directly targeted by PXR. These findings may explain the diabetogenic effects of certain medications and environmental contaminants, positioning PXR in a potential novel diabetogenic pathway. At physiological concentrations found in the liver, glucose binds to and activates the transcriptional activity of LXRs, inducing the expression of LXR target genes with similar efficacy to that of oxysterols, which are well-known LXR ligands. Cholesterol homeostasis genes, which depend on LXR for their expression, were upregulated in the liver and intestines of fasted mice after refeeding with a glucose-rich diet, 278 suggesting that glucose acted as an endogenous ligand for LXR.

Nuclear orphan receptor subfamily 4 group A member 1 (NR4A1), an important regulator of hepatic glucose homeostasis, was found to interact with the nuclear glycerol kinase Gyk during hepatic gluconeogenesis in the unfed state and in diabetes. Gyk acts as a corepressor of NR4A1, which attenuates the expression of target genes involved in hepatic gluconeogenesis and obstructs blood glucose regulation. 279 Nuclear receptor subfamily 5 group A member 2 (NR5A2 or LRH1) and steroidogenic factor 1 (SF1 or NR5A1) work synergistically as key regulators of glucose-sensing systems in hepatic and steroidogenic tissues. 280 These receptors are essential for the normal processing of glucose after eating through direct control of GCK and HK1 transcription. 281 FXR combines signals from PKA and FOXA2 for hepatic glucose metabolism and production through two regulatory arms. 282 The first is the phosphorylation of FXR by protein kinase A, which induces glucagon, agonist-activated FXR and CREB to combine and activate gluconeogenic genes. The physical interaction between FXR and the glucagon-activated FOXA2 transcription factor constitutes the second arm, which prevents FXR from stimulating the anti-gluconeogenic nuclear receptor SHP. Foxa2 knockdown did not influence the expression of glucagon-induced or FXR agonist-boosted gluconeogenic genes, suggesting that distinct subsets of FXR-sensitive genes are controlled by the PKA and FOXA2 pathways. 282

NR coregulators play crucial roles in the regulation of glucose metabolism. For example, NR corepressors (NCoRs) operate within multiprotein complexes containing histone deacetylase 3 (HDAC3) to inhibit transcription, primarily through repressive chromatin remodeling at target loci. This process ultimately drives glucocorticoid receptor-dependent activation of hepatic gluconeogenesis. In hepatocytes, the double knockout of both NCoR1 and NCoR2 mimicked the hepatomegaly and fatty liver phenotype observed in HDAC3 knockouts by preventing glucocorticoid receptor binding. 283 Similarly, nuclear receptor coactivator 3 (NCOA3) regulates the transcription of tyrosine-protein kinase (Fyn) in a PPARγ-dependent manner. NCOA3 deficiency was shown to worsen diabetic kidney disease by exacerbating albuminuria, glomerular sclerosis, and podocyte injury and impairing autophagy. 284

Bile acid, sterol and lipid metabolism

Increasing evidence suggests that NRs play critical roles not only in glucose metabolism but also in the regulation of sterol, bile acid and lipid metabolism. 285 – 287 The three ERR isoforms, as well as PPARα and PPARδ, are the main transactivators of genes involved in mitochondrial bioenergetics and fatty acid oxidation (FAO) and are viewed as primary controllers of mitochondrial FAO. 288 , 289 For example, in addition to being a regulator of mitochondrial function, ERRα was established as a major transcriptional regulator of lipid biosynthesis and a promoter of nonalcoholic fatty liver disease (NAFLD/NASH). 290 Medium-chain specific acyl-CoA dehydrogenase ( ACADM ), the first-discovered target gene of ERRα, encodes the initial rate-limiting enzyme in mitochondrial FAO; the promoter is also targeted by PPARα. 291 In addition, a muscle-specific protein induced by PGC-1 and ERRs, PERM1 (PGC-1/ERR-induced regulator in muscle-1), promoted mitochondrial biogenesis and metabolism in cardiomyocytes. In this study, PERM1 was shown to interact with the proximal regions of PPAR response elements (PPREs) in the endogenous promoters of genes involved in fatty acid oxidation, and further results revealed that PERM1 interacted with PPRE to promote transcription, partly in a PPARα- and PGC-1α-dependent manner. 292

PPARα is also a key regulator of fatty acid oxidation and can induce spontaneous fatty liver and hyperlipidemia in mice fed a standard diet. For example, during the early night, fasting mice exhibited acute PPARα-dependent hepatocyte activity, accompanied by increased circulating free fatty acids that could be further stimulated by adipocyte lipolysis. However, fasting resulted in mild hypoglycemia and hypothermia in PPARα hep−/− mice, suggesting a role of PPARα activity in nonhepatic tissues. 293 Liver-specific inactivation of Vps15, the essential regulatory subunit of class 3 PI3K, elicited mitochondrial depletion and failure to oxidize fatty acids through blunting of the transcriptional activity of PPARα. Vps15 deficiency led to the accumulation of the PPARα repressors HDAC3 and nuclear receptor corepressor 1 (NCoR1) in the liver due to disrupted autophagy. Activation of PPARα or inhibition of HDAC3 restored mitochondrial biogenesis and FAO in Vps15-deficient hepatocytes, revealing functions for class 3 PI3K and autophagy in the transcriptional coordination of mitochondrial metabolism. 294 In addition, hepatic Ncor1 deletion in mice retarded atherosclerosis development by reprogramming bile acid metabolism and enhancing fecal cholesterol excretion, resulting in reduced plasma cholesterol levels and decreased hepatic cholesterol content in liver-specific Ncor1 knockout mice compared with those in controls fed an atherogenic diet for twelve weeks. 295

NR4A1 was identified as a previously unrecognized constitutive regulator of adipocyte progenitor (AP) quiescence. 296 In ex vivo experiments, NR4A1 gain-of-function reduced adipogenesis, whereas its loss-of-function increased adipogenesis. 296 Compared with control mice, NR4A1 knockout mice fed a high-fat diet were more prone to obesity, with increased gene expression of PPARγ and FAS. Conversely, NR4A1 overexpression in 3T3-L1 preadipocytes inhibited adipogenesis. NR4A1 upregulated GATA binding protein 2 (GATA2), which in turn inhibited PPARγ. NR4A1 also suppressed sterol regulatory element-binding protein 1 (SREBP1) and its downstream target fatty acid synthase (FAS) by upregulating p53. Overall, NR4A1 inhibits adipocyte differentiation and lipid accumulation by increasing the expression of GATA2 and p53. 297 Nuclear receptor subfamily 0 group B member 2 (NR0B2, also called SHP) is expressed at high levels in the liver and intestine, and its transcriptional activity can be increased by fibroblast growth factor 19 (human FGF19, mouse FGF15) signaling. FGF19 and SHP were observed to inhibit SREBF2 (sterol regulatory element binding transcription factor 2), which led to a reduction in intestinal NPC1L1 expression, cholesterol absorption and hypercholesterolemia. 298 Another member of the nuclear receptor family, NR1A1, was reported to influence hepatic autophagy, lipid metabolism and adipocyte homeostasis by interacting with MED1 through a bridge formed by PGC1α. 299 , 300

The expression of RORα/β/γ and REV-ERBα/β in the liver follows circadian rhythms. The liver genome contains high-order transcriptionally repressive hubs where REV-ERBα condensates are found, and these hubs are strongly associated with circadian gene repression. 301 – 303 In mouse models, RORs bind to ROREs at night, whereas REV-ERBα/β bind to ROREs during the day to decrease lipogenesis. In the liver, REV-ERBα and REV-ERBβ work in concert, increasing the ability of HDAC3 and NCoR to control SREBP activity and maintain lipid homeostasis. They also affect cytochrome P4507A1 expression levels, which helps to maintain the equilibrium of bile acid metabolism. 304 RORγ serves as a crucial activator of the entire cholesterol biosynthesis program, controlling SREBP2 by binding to genes involved in cholesterol biosynthesis and facilitating SREBP2 recruitment. At the loci of genes involved in cholesterol production, RORγ inhibition decreases chromatin acetylation and disrupts its connection with SREBP2. In immunocompetent animals and patient-derived xenografts, RORγ antagonists induce tumor regression. 305

The regulation of bile acids, sterols and lipids is also associated with many other types of nuclear receptors. Through the regulation of Akr1b7 transcription, the nuclear receptor PXR effectively reduces AKI by increasing reactive oxygen species (ROS) generation, mitochondrial autophagy and mitochondrial dysfunction in lipid metabolism. 306 It was recently demonstrated that the function of FXR in BA homeostasis depends on the phosphorylation of Tyr-67 by the FGF15/19 signaling-activated nonreceptor tyrosine kinase Src. According to Byun and colleagues, hepatic FXR phosphorylation by FGF15/19-induced Src preserves cholesterol homeostasis and protects against atherosclerosis. 307 PXR activation upregulated intermediates in the Kandutsch–Russell cholesterol synthesis pathway in the liver and induced a number of cholesterol synthesis genes, including the rate-limiting HMRCR. In both mice and humans, PXR activation increased the level of plasma proprotein convertase subtilisin/kexin type 9 (PCSK9), a negative regulator of hepatic LDL absorption. A new regulator of PCSK9 and cholesterol synthesis, the PXR-SREBP2 pathway, also serves as a molecular mechanism for drug- and chemical-induced hypercholesterolemia. 308

Mitochondria, OxPhos and the TCA cycle

Mitochondria serve as vital energetic and biosynthetic signaling hubs, taking in substrates from the cytoplasm to generate bioenergetic and biosynthetic building blocks. 309 This process is achieved through the coordinated activity of several key metabolic pathways, including the electron transport chain (ETC), oxidative phosphorylation (OxPhos), the tricarboxylic acid (TCA) cycle, glycolysis, glutaminolysis and fatty acid oxidation (FAO). These pathways not only produce ATP but also provide intermediates essential for biosynthesis. Crucially, the function of mitochondria is tightly regulated by various nuclear receptors, which modulate gene expression to ensure proper mitochondrial activity and metabolic balance.

Several nuclear receptors are involved in regulating genes associated with the TCA cycle and OxPhos, including estrogen-related receptor alpha (ERRα), NUR77 (NR6A1) and PPARγ. 310 – 312 One of the first major datasets used to highlight the role of ERRα in OxPhos regulation was a study that integrated PGC1α-induced GW transcriptional profiling with a software approach to identify cis-regulatory sequences. 313 , 314 Mice lacking both ERRα and ERRγ presented the most extensive and profound disruption in skeletal muscle gene expression, with the ‘mitochondrial function’ pathway genes involved in OxPhos and the TCA cycle being the most significantly affected. Moreover, mice deficient in ERRβ and ERRγ exhibit impairments in lipid metabolism and branched-chain amino acid metabolism, specifically in the soleus muscle. 315 Similarly, muscle-specific deletion of Esrrg (the gene encoding ERRγ) in mice reduces exercise capacity because of deficient mitochondrial activity. 316 adipocytes lacking all ERR isoforms exhibited significant downregulation of genes involved in oxidative metabolic pathways, including those controlling the TCA cycle and OxPhos, leading to marked reductions in mitochondrial content and oxidative capacity. 317 These results suggest that many mitochondrial actions are mediated through the stimulation of ERR expression and activity, underscoring the critical role of ERR in mitochondrial energy metabolism across various tissues.

The nuclear receptor Nur77 (also known as TR3 or NGFI-B), encoded by Nr4a1 , belongs to the steroid/thyroid/retinoid superfamily and serves as a key regulator of energy metabolism. Nur77 is phosphorylated by ERK2 and translocated to the mitochondria upon glucose deprivation. Mitochondrial Nur77 binds to TPβ, a rate-limiting enzyme in FAO, to protect it from oxidation. This promoted the metabolic adaptation of melanoma cells by evading ROS-induced cell death. 318 Ubiquitinated mitochondrial Nur77 interacts with the ubiquitin-binding domain of p62/SQSTM1 to form condensates capable of sequestering damaged mitochondria. An additional interaction between the N-terminal intrinsically disordered region (IDR) of Nur77 and the N-terminal PB1 domain of p62/SQSTM1 allows tethering of clustered mitochondria to the autophagy machinery, which endows Nur77-p62/SQSTM1 condensates with the magnitude and liquidity to act on the mitochondria. 319 In response to the pathological accumulation of α-synuclein (α-syn) fibrils in Parkinson’s disease (PD), Nur77 is translocated from the cytoplasm to the mitochondria to improve PHB-mediated mitophagy by regulating c-Abl phosphorylation. Nur77 overexpression alleviated the expression of pS129-α-syn and protected dopamine (DA) neurons from the loss of α-syn in PD. 320

NR1D1 (nuclear receptor subfamily 1 group D member 1) is the most highly upregulated nuclear receptor in abdominal aortic aneurysm (AAA) tissues. Knockout of Nr1d1 in vascular smooth muscle cells (VSMCs), but not in endothelial or myeloid cells, led to significant inhibition of AAA formation. Mechanistic investigations revealed that ACO2 (aconitase-2), a key enzyme in the TCA cycle, is a direct transcriptional target of NR1D1. By repressing ACO2, NR1D1 modulates mitochondrial metabolism. In the absence of NR1D1, ACO2 expression is restored, which subsequently corrects mitochondrial dysfunction during the early stages of Ang II infusion, even prior to the onset of AAA development. 321

Catabolism of amino acids

Amino acid catabolism is vital during starvation to sustain glucose levels and provide alternative carbon sources, primarily in the liver but also in the kidneys, muscles and adipose tissue. 322 This process involves transamination and oxidative deamination in the cytoplasm, producing metabolites such as α-ketoglutarate, pyruvate and acetyl-CoA, which feed into the TCA cycle. 323 An essential NR in AA catabolism is ERRα, which is active in regulating genes involved in amino acid uptake and branched-chain amino acid metabolism. 324 ERRα is also linked to reduced leucine oxidation under energy-demanding conditions. 325 PPARα and HNF4α also regulate amino acid utilization. PPARα, in the presence of RXRα, inhibited HNF4α activity, suppressing serine dehydratase expression by promoting HNF4α degradation via the proteasome pathway. In PPARα-knockout mice, HNF4α levels and amino acid catabolizing enzyme (AACE) expression are elevated. 326 In response to amino acid deficiency (AAD), MEF2D (myocyte enhancer factor 2D) and NR4A1 induce FAM134B2 expression and promote FAM134B2-mediated reticulophagy to maintain intracellular amino acid levels. 327

Inflammation and immunity

Compelling evidence suggests that NRs can regulate inflammation and immunity, contributing to the pathogenesis of human diseases. For example, Nur77 binds to LPS, acting as an LPS receptor protein and playing a role in macrophage pyroptosis. Further research indicated that Nur77-LPS interactions activated NLRP3, resulting in the formation of an atypical inflammasome. These findings demonstrated that Nur77 promotes NLRP3 inflammasome activation, enhancing the host immune response to endotoxins. 174 Similarly, Nur77 was identified as a key transcriptional regulator of the proinflammatory metabolic switch in macrophages. IDH expression was not downregulated in Nur77-deficient macrophages, which led to increased levels of succinate and other TCA cycle metabolites, independent of glutamine, resulting in increased nitric oxide and proinflammatory cytokine production in an SDH-dependent manner. Thus, Nur77 promotes an anti-inflammatory metabolic state in macrophages, offering protection against chronic inflammatory diseases such as atherosclerosis. 328 Another nuclear receptor, RORα, regulates hepatic macrophage polarization and inflammation by inducing kruppel-like factor 4 (KLF4) expression. In myeloid-specific RORα-deficient animals, Kupffer cells (KCs) and bone marrow-derived macrophages fail to undergo M2 polarization, rendering them more susceptible to high-fat-diet-induced nonalcoholic steatohepatitis (NASH). 329 Additionally, the orphan nuclear receptor TLX directly bound to the CD274 (PD-L1) gene promoter, showing a strong positive correlation with PD-L1 overexpression. Suppressing TLX significantly reduced the in vivo growth of glioma allografts and xenografts, preserved the antitumor immune response and markedly decreased the number of PD-L1-positive cells and glioma-associated macrophages. 330 Nuclear receptor subfamily 1 group D member 1 (NR1D1) acts as a transcriptional repressor and plays a key role in regulating inflammation. The activation of NR1D1 decreased the expression of proinflammatory cytokines and matrix metalloproteinases (MMPs), whereas NR1D1 silencing had the opposite effect. Additionally, NR1D1 activation reduces ROS production and increases the generation of Nrf2-associated antioxidant enzymes. 331

NRs also play crucial roles in modulating immune responses by directly regulating the function and activity of immune cells, such as influencing their development, differentiation and activation. For example, overexpression of NR4A1 inhibited the development of effector T cells through binding to the transcription factor AP-1 and inhibited its promotion of the expression of effector genes. NR4A1 binding encouraged the acetylation of histone 3 at lysine 27 (H3K27ac), which activated genes linked to tolerance. Deletion of NR4A1 increases immunity against tumors and chronic viruses, overcomes T-cell tolerance and enhances effector function. 332 Similarly, another study revealed that NR4A triple knockout CAR-T lymphocytes presented traits and gene expression profiles typical of CD8 + effector T cells. The chromatin regions in these cells were enriched in binding motifs for transcription factors involved in T-cell activation, such as NF-κB and AP-1. 333 These studies suggest that NR4A is a major regulator involved in the induction of T-cell dysfunction and that NR4A inhibition is a promising approach for cancer immunotherapy.

RARs and RA signaling play crucial roles in immune responses, influencing immune tolerance, tissue homing, lymph node formation and protective immunity. 334 RARs include RARα, RARβ and RARγ, which are encoded by different genes with unique transcriptional variants and isoforms. In the resting state, RARα binds to transcriptional repressors to inhibit gene expression. However, upon binding to RA, RARα tends to bind to transcriptional activators, promoting gene expression 334 RAR signaling has been shown to regulate immunity. For example, following TCR stimulation, extranuclear RARα is rapidly phosphorylated and recruited to the TCR signalosome. RA disrupted extranuclear RARα signaling, leading to reduced TCR activation and increased conversion of FOXP3+ regulatory T cells. RA is translocated to the nucleus by CRABP2, which is upregulated by TCR activation. Deletion of Crabp2 resulted in increased cytoplasmic RA, disrupting signalosome-associated RARα and consequently weakening autoimmune responses while diminishing antipathogen immunity. 335

Temporal expression changes

The expression of nuclear receptors is not only related to tissue, sex, and disease but also varies across different age groups within the same individual. 336 These variations reflect developmental needs, metabolic changes, hormonal shifts, and adaptations to aging-related physiological demands. Generally, developmental NRs such as RARs, PPARs and RXRs are highly expressed during embryogenesis and early development to support rapid growth, differentiation, and development. 337 During adolescence, ARs, ERα and ERβ are elevated to correlate with puberty and the onset of secondary sexual characteristics, whereas GRs act to moderate stress responses and energy metabolism during periods of rapid physical and emotional development. PPARs, LXRs, and FXRs live in adult individuals to maintain lipid and glucose homeostasis, supporting metabolic stability during peak years of physical activity and reproductive capability. Diet, exercise, and stress significantly modulate NR expression, affecting metabolic and endocrine balance during this period. The expression of these NRs decreases with increasing age, which causes impaired lipid metabolism and insulin sensitivity, cholesterol and bile acid metabolism, and calcium homeostasis and immune function, leading to an increased risk of metabolic syndrome, compromised organ function and chronic inflammation. For example, Nr4a1 is reduced in peripheral blood mononuclear cells and CA1 pyramidal neurons with aging, which impairs cognition and excitatory synaptic function. 338 Monitoring age-specific NR expression patterns could guide personalized therapies to optimize metabolic health and prevent age-related diseases.

Degradation and metabolic cycling

The metabolic cycling process of NRs, including their synthesis, activation, degradation, and recycling, is integral to maintaining homeostasis and ensuring that NRs can adapt to changing physiological demands. Since the activation and transcriptional regulation of nuclear receptors have been discussed above, we mainly emphasize their degradation and recycling. The degradation of nuclear receptors is a highly regulated process that involves proteasomal and lysosomal pathways, ensuring the dynamic control of receptor levels in response to physiological and environmental cues. Ligand binding can either stabilize or destabilize NRs by inducing conformational changes that influence ubiquitination. 339 , 340 In addition, posttranslational modifications (PTMs), such as phosphorylation, 341 SUMOylation 342 and acetylation, 343 modify NR degradation rates by altering their interaction with ubiquitin ligases or stabilizing proteins. Moreover, many NRs, such as REV-ERBs and PPARs, exhibit circadian cycling, with their expression and activity oscillating in a 24-hour rhythm to align with metabolic needs. 344 , 345 These rhythms are coregulated by core circadian clock genes (e.g., CLOCK and BMAL1), which synchronize metabolic functions with environmental cycles such as light and feeding. Altogether, cycling of NRs ensures appropriate receptor levels, preventing excessive or prolonged signaling that could lead to cellular dysfunction.

Alterations cause by aging

With aging, the efficiency of key regulatory pathways declines, leading to altered NR turnover, disrupted signaling, and increased susceptibility to age-related diseases. 346 Proteasomal dysfunction, a hallmark of aging, impairs the degradation of damaged or misfolded proteins, including NRs. This results in the accumulation of inactive or malfunctioning receptors, which disrupt signaling and contribute to metabolic and endocrine dysregulation, key features of aging. These disruptions play a central role in the development of diseases such as obesity, diabetes, cardiovascular conditions, and neurodegenerative disorders. 347 , 348 Additionally, aging reduces autophagic flux, hindering the clearance of damaged proteins, including aggregated NRs. As autophagy becomes less efficient with age, NR aggregates persist, disrupting receptor signaling and promoting chronic inflammation, mitochondrial dysfunction, and cellular stress. 349 , 350 These factors are implicated in the progression of age-related diseases like Alzheimer’s, diabetes, and frailty. Oxidative stress also contributes to aging-related cellular damage by directly modifying NRs. ROS cause conformational changes in NRs, preventing their proper ubiquitination and degradation. This oxidation makes NRs resistant to degradation, leading to the accumulation of damaged receptors and further dysfunction in signaling pathways. 351 Understanding these age-related changes offers valuable insights for developing targeted therapies to restore NR homeostasis and mitigate aging-associated disorders.

Targeting nuclear receptors for disease management

Given the critical role of NRs in physiological and pathological processes, they constitute a highly significant and privileged class of intracellular druggable targets for treating various diseases. 52 , 352 – 354 By modulating these receptors, it is possible to influence a wide range of conditions, from metabolic disorders such as diabetes and obesity to immune-related diseases such as autoimmune disorders and inflammatory conditions (Tables 1 , 2 ). NRs are central to cancer progression and hormone regulation, making them prime targets for oncology and hormone therapies. The ability to design drugs that specifically interact with nuclear receptors enhances their potential for precision medicine, offering more targeted treatments with fewer side effects across a broad spectrum of diseases. Table 1 Summary of completed clinical trials of nuclear receptor-targeted drugs Target NCT Number Results Conditions Agents Phases Retinoic acid receptor-α (RARα) NCT02273102 COMPLETED (No Results Posted) Acute Myelogenous Leukemia; Myelodysplastic Syndromes; Leukemia Tranylcypromine; Tretinoin PHASE1 Retinoic acid receptor-γ (RARγ) NCT02521792 TERMINATED (The study was stopped prematurely and due to the small number of evaluable subjects, there was insufficient data to conduct any efficacy analyses. Consequently, no summary statistics are available for any of the secondary outcome measures) Fibrodysplasia Ossificans Progressiva Palovarotene PHASE2 NCT02190747 COMPLETED (Supporting further evaluation of palovarotene for prevention of HO in FOP in larger studies 491 ) Fibrodysplasia Ossificans Progressiva (FOP) Palovarotene; Placebo PHASE2 NCT02279095 COMPLETED (RAR-γ agonists are potent inhibitors of heterotopic ossification in mouse models 492 ) Fibrodysplasia Ossificans Progressiva Palovarotene PHASE2 Peroxisome proliferator-activated receptor-α (PPARα) NCT00809068 COMPLETED (No Results Posted) HDL Cholesterol Fenofibrate and tibolone; Tibolone PHASE4 NCT03662984 COMPLETED (No Results Posted) Myocardial Insulin Sensitivity; Impaired Glucose Metabolism; Diastolic Dysfunction Ciprofibrate 100Mg Tablet; Placebo Oral Tablet PHASE3 NCT03345901 TERMINATED (No Reason Posted) Diabetic Retinopathy; Diabetic Macular Edema Pemafibrate; Placebo PHASE3 NCT03829436 COMPLETED (No Results Posted) Hepatocellular Carcinoma; Metastatic Castration; Resistant Prostate Cancer; Renal Cell Carcinoma; Non-small Cell Lung Cancer;Colorectal Cancer;Squamous Cell Carcinoma of Head and Neck;Triple-Negative Breast Cancer; Urothelial Carcinoma; Cholangiocarcinoma; GastroEsophageal Cancer; Pancreatic Cancer; Sarcoma Part 1 TPST-1120; Part 2 TPST-1120 + nivolumab; Part 3 TPST-1120; Part 4 TPST-1120 + nivolumab PHASE1 NCT00483210 WITHDRAWN (Study results have not been submitted. This may be because the study is not done, the deadline for submitting results has not passed, this study is not required to submit results, or the sponsor or investigator has requested or received a certification to delay submitting the results) Tissue Lipid Metabolism Fenofibrate NA Peroxisome proliferator-activated receptor-β/δ (PPAR-βδ) NCT03040856 WITHDRAWN (Study results have not been submitted. This may be because the study is not done, the deadline for submitting results has not passed, this study is not required to submit results, or the sponsor or investigator has requested or received a certification to delay submitting the results) Omega 3 Supplements During Pregnancy Alpha Linolenic Acid; Omega 3 enriched diet (DHA + EPA); OTHER: Placebo NA Peroxisome proliferator-activated receptor-γ (PPAR-γ) NCT03080480 TERMINATED (No Reason Posted) Chronic Granulomatous Disease Pioglitazone PHASE1; PHASE2 NCT00166803 SUSPENDED (No Reason Posted) Diabetes Mellitus, Atherosclerosis Rosiglitazone NA NCT00408434 COMPLETED (Efatutazone demonstrates acceptable tolerability in patients with advanced malignancies) Neoplasm Efatutazone PHASE1 NCT02774343 COMPLETED (No conclusion) Cocaine Use Disorder; Alcohol Use Disorder Pioglitazone; Placebo; PHASE1; PHASE2 NCT00603941 TERMINATED (The study was halted prematurely due to low enrollment and failure to establish recommendation of Phase 2 dose. Analysis for the primary efficacy outcomes were also combined for the study) Anaplastic Thyroid Cancer CS-7017; Paclitaxel PHASE1; PHASE2 NCT00193648 COMPLETED (No Results Posted) Focal Glomerulosclerosis Rosiglitazone (Avandia); Adalimumab (Humira) PHASE1 NCT00407862 COMPLETED (No Results Posted) Hypertension; Impaired Glucose Tolerance Telmisartan 80 mg; Losartan 50 mg PHASE4 NCT06266598 COMPLETED (No Results Posted) Childhood Obesity; Insulin Resistance Metformin PHASE4 NCT03231033 COMPLETED (No Results Posted) Autoimmune Pulmonary Alveolar Proteinosis Pioglitazone PHASE1 NCT00285805 COMPLETED (No Results Posted) Insulin Resistance Rosiglitazone versus placebo NA NCT01068444 COMPLETED (No Results Posted) Hepatitis Pioglitazone; placebo PHASE2 NCT02694874 COMPLETED (No Results Posted) Malaria Rosiglitazone; Placebo NA NCT01395784 COMPLETED (No conclusion) Opioid Abuse Pioglitazone PHASE2 NCT01019356 COMPLETED (No Results Posted) Polycystic Ovary Syndrome Rosiglitazone; Acarbose NA NCT02696577 COMPLETED (No Results Posted) Intrauterine Growth Restriction Low dose aspirin; Omega 3 PHASE2 NCT00452192 COMPLETED (No Results Posted) Metabolic Syndrome Telmisartan PHASE3 NCT00868140 TERMINATED (No Reason Posted) Polycystic Ovary Syndrome Pioglitazone; Placebo NA NCT03868566 TERMINATED (No Reason Posted) NASH-Nonalcoholic Steatohepatitis SNP-612 dose1; SNP-612 dose2 PHASE2 NCT02444910 COMPLETED (No Results Posted) Diabetes Mellitus, Type 2 KDT501 PHASE2 NCT01589445 COMPLETED (No conclusion) Type 2 Diabetes Mellitus Pioglitazone hydrochloride; Metformin hydrochloride PHASE4 NCT03864523 COMPLETED (No Results Posted) Adrenomyeloneuropathy; X-linked Adrenoleukodystrophy Pioglitazone PHASE2 Farnesoid X receptor (FXR) NCT01492998 TERMINATED (No Reason Posted) Chronic Hepatitis C Guggulsterone NA NCT02654236 COMPLETED (No conclusion) Alcohol Consumption Placebo; 10 mg Obeticholic Acid (OCA) NA NCT03272009 COMPLETED (No Results Posted) Hepatitis B, Chronic EYP001a; Placebo; PHASE1 Entecavir; peg-interferon alfa-2a NCT01625026 COMPLETED (No Results Posted) Obesity; Gallstones Obeticholic acid; Placebo PHASE2 NCT01265498 COMPLETED (No conclusion) Nonalcoholic Fatty Liver Disease (NAFLD); Nonalcoholic Steatohepatitis (NASH) Obeticholic acid; placebo PHASE2 NCT01585025 COMPLETED (No conclusion) Primary Bile Acid Malabsorption; Secondary Bile Acid Malabsorption; Chronic Diarrhea Obeticholic acid PHASE2 NCT04365933 COMPLETED (No Results Posted) Hepatitis B, Chronic EYP001a; Entecavir; Pegylated interferon alpha2a PHASE2 NCT04465916 TERMINATED (No Reason Posted) Hepatitis B, Chronic EYP001a; Placebo; Nucleotide analog (Entecavir or Tenofovir Disoproxil) PHASE2 NCT02430077 COMPLETED (No conclusion) Familial Partial Lipodystrophy Obeticholic Acid; Placebo PHASE2 NCT00465751 COMPLETED (No Results Posted) Metabolic Syndrome; Familial Hypertriglyceridemia; Familial Combined Hyperlipidemia Chenodeoxycholic acid; Placebo capsules EARLY_PHASE1 NCT03320616 COMPLETED (No Results Posted) Hepatitis B, Chronic EYP001a PHASE1 NCT05450887 COMPLETED (No Results Posted) Primary Biliary Cholangitis Obeticholic Acid Tablets; UDCA; Placebo PHASE3 NCT02855164 TERMINATED (No outputs were planned; and are not available for determining the effects of tropifexor on primary endpoints in the subset of patients who had historical biopsy data) NASH Tropifexor (LJN452); Placebo PHASE2 NCT01999101 COMPLETED (No Results Posted) NAFLD Px-104 PHASE2 NCT05321524 TERMINATED (No Reason Posted) Biliary Atresia OCA 0.1 mg; OCA 1.5 mg; OCA 5 mg PHASE2 NCT05203367 WITHDRAWN (Study results have not been submitted. This may be because the study is not done, the deadline for submitting results has not passed, this study is not required to submit results, or the sponsor or investigator has requested or received a certification to delay submitting the results) NAFLD BAR502; Placebo PHASE1 NCT03469583 COMPLETED (No conclusion) Hepatitis B, Chronic EYP001; Entecavir 1 MG PHASE1 NCT05591079 COMPLETED (No Results Posted) NASH CS0159 (Linafexor) PHASE2 NCT05604287 TERMINATED (No Reason Posted) Healthy Participants ID119031166M; Placebo PHASE1 NCT04408937 COMPLETED (No Results Posted) Liver Disease Triopifexor; Placebo PHASE1 NCT02158351 COMPLETED (No Results Posted) Simple Steatosis (SS); Obesity; NASH PROCEDURE: liver and white adipose tissue biopsies NA NCT02177136 COMPLETED (Treatment with OCA 5-10 mg reduced serum alkaline phosphatase in patients with PSC 493 ) Primary Sclerosing Cholangitis (PSC) Obeticholic Acid (OCA); Placebo PHASE2 NCT02713243 COMPLETED (Tropifexor had acceptable safety and tolerability and exhibited therapeutic potential 494 ) Primary Bile Acid Diarrhea LJN452; Placebo to LJN452 PHASE2 NCT04328077 COMPLETED (No conclusion) NASH TERN-101; Placebo PHASE2 NCT03270527 COMPLETED (No Results Posted) Lipids; Lipid Metabolism; Healthy High SFA diet (Diet 1); Low SFA diet (Diet 2) NA NCT03598920 COMPLETED (No Results Posted) Obesity, Morbid Asspire Assist; Nutritional consulting NA NCT05415722 COMPLETED (No Results Posted) NASH TERN-501; TERN-101; Placebo PHASE2 NCT00550862 TERMINATED (No Reason Posted) Liver Cirrhosis, Biliary INT-747; Ursodeoxycholic Acid (URSO); Placebo PHASE2 NCT02308111 TERMINATED (The estimated effect of treatment from the ITT population was underpowered and potentially biased, resulting in difficulties in the interpretation of the tests of hypotheses for the primary and key secondary endpoints) Liver Cirrhosis, Biliary Obeticholic Acid (OCA); Placebo PHASE4 NCT00501592 COMPLETED (25 or 50 mg OCA s was well tolerated, increased insulin sensitivity, and reduced markers of liver inflammation and fibrosis 495 ) Diabetes Mellitus, Type II; Fatty Liver INT-747; Placebo PHASE2 NCT03836937 COMPLETED (No Results Posted) NAFLD Obeticholic acid NA NCT02430077 COMPLETED (No Results Posted) Familial Partial Lipodystrophy Obeticholic Acid; Placebo PHASE2 NCT05415722 COMPLETED (No Results Posted) NASH TERN-501; TERN-101; Placebo PHASE2 Vitamin D receptor (VDR) NCT04847947 COMPLETED (No Results Posted) Prefrail Elderly Cholecalciferol; Placebo PHASE3 NCT00677534 COMPLETED (No Results Posted) End-Stage Renal Disease Cholecalciferol NA NCT01265615 COMPLETED (No Results Posted) Cardiorenal Syndrome; Chronic Allograft Nephropathy Paricalcitol; Calcitriol; Cholecalciferol PHASE4 NCT03331562 COMPLETED (No Results Posted) Pancreatic Cancer; Pancreas Adenocarcinoma; Advanced Pancreatic Cancer; Metastatic Pancreatic Cancer; Metastatic Pancreatic Adenocarcinoma Pembrolizumab; paricalcitol; placebo PHASE2 NCT04140292 COMPLETED (Oral VD3 pretreatment significantly improves actinic keratoses clinical responses to PDT 496 ) Actinic Keratosis Photodynamic therapy (PDT); Vitamin D3 PHASE2 NCT00301067 COMPLETED (No Results Posted) Metastatic Melanoma DIETARY_SUPPLEMENT: Calcitriol; Temozolomide PHASE1; PHASE2 NCT00507442 COMPLETED (VDR and VCD-mod are preferred for clinical practice and further comparative testing 497 ) Multiple Myeloma VELCADE (bortezomib); dexamethasone; cyclophosphamide; Revlimid (lenalidomide) PHASE1; PHASE2 NCT02931162 COMPLETED (No Results Posted) Ulcerative Colitis OTHER: Herb-partitioned moxibustion; OTHER: Sham herb-partitioned moxibustion NA NCT01084538 COMPLETED (No Results Posted) Parathyroid Hormone Zemplar iv (paricalcitol iv) NA NCT01092130 COMPLETED (Six weeks of supplementation with 2,000 IU VitD3 increased 25-hydroxyvitamin D3 levels and decreased PRA and plasma renin concentration 498 ) Chronic Heart Failure Vitamin D PHASE2 NCT01447355 COMPLETED (No Results Posted) Healthy, no Evidence of Disease; Skin Cancer Cholecalciferol PHASE1 NCT02856503 WITHDRAWN (Study results have not been submitted. This may be because the study is not done, the deadline for submitting results has not passed, this study is not required to submit results, or the sponsor or investigator has requested or received a certification to delay submitting the results) Breast Cancer; Ductal Carcinoma In situ Vitamin D3 PHASE1; PHASE2 NCT02282800 COMPLETED (No Results Posted) Aggressive Periodontitis GENETIC: Vitamin D receptor NCT03602430 COMPLETED (Cholecalciferol was effective, tolerable, inexpensive pharmacotherapeutic option to overcome vitamin D deficiency 499 ) Hemodialysis Complication; Vitamin D Deficiency; Vascular Calcification Cholecalciferol; Placebo PHASE2; PHASE3 NCT05753280 COMPLETED (No Results Posted) Chronic Hepatitis b Vitamin D PHASE4 NCT01222234 COMPLETED (No Results Posted) Chronic Kidney Disease (CKD); End-stage Renal Disease (ESRD) Cholecalciferol - CKD; DEVICE: Calcitriol - CKD; Cholecalciferol - non-CKD NA NCT00585442 TERMINATED (No Reason Posted) Hypertension; Vitamin D Deficiency Calcitriol; Placebo EARLY_PHASE1 NCT00084864 TERMINATED (Study was activated prior to Roswell Park Cancer Institute (RPCI) putting a system in place to centralize data entry and data management. Data entry was done by PI’s staff. PI left institute and left incomplete data) Prostate Cancer DIETARY_SUPPLEMENT: calcitriol; dexamethasone; clinical observation PHASE2 NCT04197089 COMPLETED (No Results Posted) Urothelial Carcinoma Vitamin D PHASE4 NCT03415854 COMPLETED (No Results Posted) Pancreatic Cancer; Pancreatic Ductal Adenocarcinoma; Pancreatic Adenocarcinoma; Pancreas Metastases; Adenocarcinoma Paricalcitol (Zemplar) PHASE2 NCT00851552 TERMINATED (Due to the study’s early termination and inadequate number of patients, no patients were analyzed) Lymphoma Rituximab; bortezomib; pegylated liposomal doxorubicin hydrochloride; PHASE2 NCT02854163 COMPLETED (No Results Posted) Psoriatic Arthritis Secukinumab PHASE2 NCT02783924 COMPLETED (No Results Posted) Vitamin D Deficiency Cholecalciferol; Placebo PHASE2 NCT01580007 COMPLETED (Adjunct therapy with PBA+vitD3 or vitD3 or PBA to standard short-course therapy demonstrated beneficial effects toward clinical recovery 500 ) Pulmonary Tuberculosis Active Sodium Phenylbutyrate and active cholecalciferol; Placebo Sodium Phenylbutyrate plus active cholecalciferol; Active Sodium Phenylbutyrate and placebo cholecalciferol; Placebo Sodium Phenylbutyrate plus placebo cholecalciferol PHASE2 NCT02527668 COMPLETED (No significant change in intramyonuclear VDR in response to either form of vitamin D vs. placebo; Type I FCSA significantly increased with VD3 501 ) Osteopenia/Osteoporosis DIETARY_SUPPLEMENT: Calcifediol; Vitamin D3; Placebo PHASE2 NCT03857893 TERMINATED (No Reason Posted) Vulvo-vaginal Atrophy; Genitourinary Syndrome of Menopause DEVICE: Dynamic Quadripolar Radio-Frequency treatment; pH-Cream NA NCT01640496 WITHDRAWN (Study results have not been submitted. This may be because the study is not done, the deadline for submitting results has not passed, this study is not required to submit results, or the sponsor or investigator has requested or received a certification to delay submitting the results) Ulcerative Colitis; Inflammatory Bowel Disease Vitamin D3; Placebo NA NCT01264874 TERMINATED (No Reason Posted) Melanoma Vitamin D3 (Colecalciferol); placebo PHASE3 NCT01325311 COMPLETED (No Results Posted) Prostate Adenocarcinoma; Stage I Prostate Cancer; Stage IIA Prostate Cancer; Stage IIB Prostate Cancer Cholecalciferol; Genistein; Placebo PHASE2 NCT00491920 COMPLETED (No Results Posted) Osteoporosis; Osteopenia Cholecalciferol (Vitamin D3); placebo PHASE4 NCT01608451 TERMINATED (No Reason Posted) Locally Advanced Breast Cancer and Large Operable Breast Cancer Cholecalciferol; Inj. Progesterone PHASE3 NCT04368520 WITHDRAWN (Study results have not been submitted. This may be because the study is not done, the deadline for submitting results has not passed, this study is not required to submit results, or the sponsor or investigator has requested or received a certification to delay submitting the results) Common Cold DIETARY_SUPPLEMENT: Vitamin D3; Vitamin D3; Placebo PHASE2 NCT01996423 COMPLETED (Weekly VD supplementation improved VD status but did not modify AD severity or type 2 immunity biomarkers 502 ) Atopic Dermatitis DIETARY_SUPPLEMENT: Vitamin D3; Placebo NA NCT02802449 COMPLETED (No Results Posted) Hypovitaminosis D 25 Hydroxy- Vitamin D3 [25 (OH) D3]; Placebo NA NCT02856776 COMPLETED (No Results Posted) Vitamin D Insufficiency DIETARY_SUPPLEMENT: Vitamin D3 NA NCT01656070 COMPLETED (No Results Posted) HIV Disease; Vitamin D Deficiency; Hypovitaminosis D; Hyperparathyroidism Oral cholecalciferol 1000000 UI (vitamin D3); Placebo PHASE2 NCT00010231 COMPLETED (No Results Posted) Prostate Cancer DIETARY_SUPPLEMENT: calcitriol; dexamethasone PHASE1 NCT04443387 COMPLETED (No Results Posted) Effect of Drug Vitamin D; Placebo NA NCT02714361 COMPLETED (No Results Posted) Iron Deficiency; Anemia; Deficiency, Nutritional, With Poor Iron Absorption; Vitamin D Deficiency DIETARY_SUPPLEMENT: Vitamin D3 supplement; Placebo NA NCT01721915 COMPLETED (No Results Posted) Polycystic Ovary Syndrome; Healthy; Vitamin D Deficiency Vitamin D supplementation; Placebo PHASE4 NCT03919812 COMPLETED (No Results Posted) Thalassemia; Tuberculosis; Vitamin D Deficiency DIETARY_SUPPLEMENT: Cholecalciferol supplementation NA NCT01304927 COMPLETED (High-dose vitamin D supplementation has beneficial effects on glucose homeostasis and HDL cholesterol levels in infertile men 503 ) Male Infertility Cholecalciferol and calcium; Placebo PHASE2; PHASE3 NCT02805231 COMPLETED (No Results Posted) Primary Open- Angle Glaucoma Vitamin D receptor polymorphic analysis NA NCT04593524 COMPLETED (No Results Posted) Tuberculosis DIETARY_SUPPLEMENT: vitamin D 1000 IU and A 6000 IU supplementation and nutritional counseling; nutritional Counseling NA NCT01204528 COMPLETED (Decline Endothelial function in patients with moderate CKD in patients with moderate CKD 504 ) Chronic Kidney Disease Zemplar PHASE2; PHASE3 NCT02276755 COMPLETED (Vitamin D supplementation did not result in a lower risk of tuberculosis infection, tuberculosis disease, or acute respiratory infection 505 ) Latent Tuberculosis DIETARY_SUPPLEMENT: Cholecalciferol (vitamin D3); Placebo PHASE3 NCT01635062 COMPLETED (No conclusion) Type 2 Diabetes; Obesity Calcitriol; Placebo NA NCT03028519 COMPLETED (No Results Posted) Ovarian Cancer Vitamin D3 EARLY_PHASE1 NCT02018133 COMPLETED (No Results Posted) CKD Stage 3/4 Vitamin D2 mg daily for 2 weeks oral paricalcitol; NA Placebo NCT05505253 COMPLETED (No Results Posted) Pelvic Organ Prolapse Alfacalcidol 0.0005 MG; Placebo PHASE3 NCT03021629 COMPLETED (No Results Posted) Vitamin D Deficiency; Primary Open-angle Glaucoma; High Myopia; Vitamin D Receptor Polymorphisms Serum levels of 1a, 25-Dihydroxyvitamin D3 were measured by an enzyme-linked immuno-absorbent assay NCT00656032 COMPLETED (No Results Posted) End Stage Renal Disease Paricalcitol; cinacalcet PHASE2 NCT01436747 COMPLETED (No Results Posted) Disorder of Transplanted Kidney; Proteinuria;Albuminuria Paricalcitol; Placebo PHASE3 NCT00587158 COMPLETED (Addition of 2 μg/day paricalcitol lowers residual proteinuria in kidney transplant recipients 506 ) Transplant; Failure, Kidney; Renal Disease, End Stage; Hyperparathyroidism, Secondary Paricalcitol; Corticosteroid Avoidance Immune Suppression Protocol NA NCT00796679 COMPLETED (52 weeks of treatment with oral paricalcitol significantly improved secondary hyperparathyroidism 507 ) Chronic Kidney Disease Paricalcitol NA NCT05376865 COMPLETED (No Results Posted) Overweight; Hypovitaminosis D DIETARY_SUPPLEMENT: Vitamin D supplement NA NCT00977080 COMPLETED (Paricalcitol versus cinacalcet plus low-dose vitamin D provided superior control of intact parathyroid hormone) Chronic Kidney Disease; Secondary Hyperparathyroidism; Hemodialysis Paricalcitol; Cinacalcet PHASE4 NCT01134315 TERMINATED (No Reason Posted) Secondary Hyperparathyroidism; End-Stage Renal Disease Paricalcitol; Calcitriol NCT01393808 COMPLETED (Paricalcitol prevents a sodium-induced increase in albuminuria 508 ) Type 2 Diabetes Paricalcitol; placebo PHASE2 NCT01197664 TERMINATED (No Reason Posted) Mucinous Adenocarcinoma of the Rectum; Stage IIA Rectal Cancer; Stage IIB Rectal Cancer; Stage IIC Rectal Cancer; Stage IIIB Rectal Cancer; Stage IIIC Rectal Cancer Paricalcitol; radiation therapy; fluorouracil PHASE1 NCT00294866 COMPLETED (No Results Posted) Kidney Failure Paricalcitol PHASE4 NCT00186901 COMPLETED (No Results Posted) Leukemia, Lymphoblastic, Acute; Osteoporosis Calcium carbonate (Tums), vitamin D; Placebo PHASE3 NCT00421733 COMPLETED (Addition of 2 μg/day paricalcitol to Addition of 2 μg/day paricalcitol to RAAS inhibition safely lowers residual albuminuria in patients with diabetic nephropathyinhibition safely lowers residual albuminuria in patients with diabetic nephropathy 509 ) Diabetic Nephropathy; Chronic Kidney Disease Zemplar (paricalcitol) capsules; Placebo PHASE2 NCT01694160 COMPLETED (There were no statistically significant differences in T50 between the paricalcitol and placebo groups 510 ) Proteinuria Paricalcitol PHASE3 NCT00208793 COMPLETED (Supplemental calcium and vitamin D3 increase TGFβ1 and TGFα expression in the normal-appearing colorectal mucosa of sporadic colorectal adenoma patient 511 ) Colorectal Adenomatous Polyps DIETARY_SUPPLEMENT: Calcium and vitamin D3 combined; Placebo; Calcium; Vitamin D3 PHASE2 NCT01371877 COMPLETED (Add-on therapy with high-dose vitamin D3 could be considered a safe and potentially beneficial immunomodulator in patients with chronic urticaria 512 ) Urticaria; Angioedema; Hives; Swelling High Dose Vitamin D3; Low Dose Vitamin D3 NA NCT01974245 COMPLETED (Restoration of vitamin D status of patients undergoing dialysis promoted upregulation of CYP27B1 and VDR expression in monocytes and a decrease in circulating inflammatory markers 513 ) Chronic Kidney Disease Cholecalciferol; Placebo PHASE2 NCT00986596 COMPLETED (No Results Posted) Sarcopenia; Falls DIETARY_SUPPLEMENT: vitamin D3; Placebo NA NCT00470353 TERMINATED (No Reason Posted) Colorectal Cancer DIETARY_SUPPLEMENT: NA Calcium carbonate; cholecalciferol; immunohistochemical staining method; laboratory biomarker analysis; pharmacological study; biopsy NCT05926570 COMPLETED (No Results Posted) Drug Effect Cinacalcet PHASE4 NCT03318029 COMPLETED (Moderate supplementation of cholecalciferol, in accordance with current recommendations, supports an adequate vitamin D status in adult women 514 ) Vitamin D Deficiency DIETARY_SUPPLEMENT: Vitamin D supplementation; Placebo NA NCT00258258 TERMINATED (No Reason Posted) Multiple Myeloma and Plasma Cell Neoplasm Paricalcitol; zoledronic acid PHASE1 NCT00217477 COMPLETED (No Results Posted) Unspecified Adult Solid Tumor Gemcitabine hydrochloride; paricalcitol PHASE1 NCT00634582 TERMINATED (No Reason Posted) Metastatic Cancer; Prostate Cancer Paricalcitol; immunoenzyme technique; laboratory biomarker analysis; PROCEDURE: Dual X-ray absorptometry; quality-of-life assessment PHASE2 Pregnane X receptor (PXR) NCT00621309 COMPLETED (No Results Posted) Adverse Drug Interactions Rifampicin; DIETARY_SUPPLEMENT: sulforaphane plus rifampicin; sulforaphane alone PHASE1 NCT02329405 COMPLETED (PXR activation elevates SBP) Nonalcoholic Fatty Liver Disease Rifampicin; Placebo PHASE4 NCT01690104 COMPLETED (PXR activation elevates SBP) Blood Pressure Regulation Rifampicin; Placebo PHASE4 NCT01293422 COMPLETED (PXR activation elevates SBP) Glucose Metabolism Rifampicin PHASE4 NCT00985270 COMPLETED (PXR activation elevates SBP) Glucose Tolerance Rifampicin; Placebo PHASE4 NCT05073627 COMPLETED (No Results Posted) Healthy Volunteers Dicloxacillin PHASE1 NCT05552196 COMPLETED (No Results Posted) Healthy Ponesimod; Carbamazepine PHASE1 NCT01550640 COMPLETED (At a dose of 1 μg/kg, remifentanil prior to induction of general anesthesia increases the risk of neonatal respiratory depression during first minutes after cesarean delivery but duration of clinical symptoms is short 515 ) Pregnancy; Cesarean Delivery; General Anesthesia Remifentanil NA NCT02629770 COMPLETED (No Results Posted) Arthritis, Infectious; Bone Diseases, Infectious Usual antibiotic treatment NA NCT01548079 COMPLETED (Ursodeoxycholic acid treatment has ambivalent effects in NAFLD patients 516 ) Nonalcoholic Fatty Liver Disease; Morbid Obesity Ursodeoxycholic Acid (UDCA) NA NCT04840641 COMPLETED (No Results Posted) Healthy Volunteers Flucloxacillin PHASE1 NCT00258258 TERMINATED (No Reason Posted) Multiple Myeloma and Plasma Cell Neoplasm Paricalcitol; zoledronic acid PHASE1 NCT00217477 COMPLETED (No Results Posted) Unspecified Adult Solid Tumor Gemcitabine hydrochloride; paricalcitol PHASE1 NCT00634582 TERMINATED (No Reason Posted) Metastatic Cancer; Prostate Cancer Paricalcitol; immunoenzyme technique; laboratory biomarker analysis; dual X-ray absorptometry; quality-of-life assessment PHASE2 Estrogen receptor-α (ERα) NCT01874756 TERMINATED (No Reason Posted) Schizophrenia LY500307 150 mg; LY500307 75 mg; Placebo; LY500307 25 mg PHASE2 Estrogen receptor-β (ERβ) NCT02067741 TERMINATED (No Reason Posted) Metastatic Breast Adenocarcinoma; Breast Cancer CR1447 PHASE2 Glucocorticoid receptor (GR) NCT00721201 COMPLETED (Mifepristone reduces insulin resistance in some individuals with adrenal incidentalomas and mild cortisol excess 517 ) Subclinical Cushing’s Mifepristone PHASE1; PHASE2 NCT01990560 COMPLETED (No Results Posted) Mild Hypercortisolism Mifepristone PHASE4 NCT05062174 WITHDRAWN (Study results have not been submitted. This may be because the study is not done, the deadline for submitting results has not passed, this study is not required to submit results, or the sponsor or investigator has requested or received a certification to delay submitting the results) BRCA1 Mutation; High-grade Serous Ovarian Cancer; TNBC - Triple- Negative Breast Cancer Mifepristone 200 MG; Prophylactic mastectomy NA NCT02989662 COMPLETED (No Results Posted) Alcohol Use Disorder Mifepristone; Placebo - Cap PHASE1; PHASE2 NCT03622112 COMPLETED (No Results Posted) Asthma AZD7594 DPI; AZD7594 DPI; AZD7594 DPI; AZD7594 DPI once daily; AZD7594 DPI; Placebo for AZD7594 once daily; FF 100 once daily (open-label) PHASE2 NCT01212588 TERMINATED (No Reason Posted) Borderline Personality Disorder Mifepristone; Placebo PHASE2 NCT03052400 TERMINATED (Administrative barriers and pandemic closures limited enrollment, curtailed several secondary outcome measures, and caused early termination of the study) Type 2 Diabetes Mellitus; Insulin Resistance Mifepristone 600 mg daily; Placebo PHASE2 NCT03697109 COMPLETED (Glucocorticoid Receptor Antagonism Upregulates Somatostatin Receptor Subtype 2 Expression in adrenocorticotropic hormone-Producing Neuroendocrine Tumors 518 ) Cushing Syndrome Relacorilant; Placebo PHASE3 NCT04588688 TERMINATED (No Reason Posted) Central Adrenal Insufficiency; Mifepristone Mifepristone PHASE2 NCT00691067 COMPLETED (A moderate dose of mifepristone may have circumscribed cognitive-enhancing effects in chronic multisymptom illness 519 ) Chronic Multisymptom illness in Gulf War Veterans Mifepristone; Placebos PHASE4 NCT03437941 COMPLETED (Enzalutamide combined with mifepristone was safe and well tolerated but did not meet its primary endpoint 520 ) Metastatic Castration-Resistant Prostate Cancer CORT125281; Enzalutamide (Xtandi); Placebo PHASE1; PHASE2 NCT02762981 COMPLETED (GR modulation in patients with adrenocorticotropic hormone-secreting neuroendocrine tumors upregulates previously suppressed SSTR2s, resulting in tumor-specific antisecretory and anti-proliferative effects 518 ) Solid Tumors Relacorilant with nab-paclitaxel PHASE1; PHASE2 NCT00285818 COMPLETED (No Results Posted) Depression Mifepristone; Placebo Oral Capsule NA NCT02012296 COMPLETED (No Results Posted) Hormone-resistant Prostate Cancer; Recurrent Prostate Cancer; Stage IV Prostate Cancer Enzalutamide; mifepristone; laboratory biomarker analysis; pharmacological study PHASE1; PHASE2 NCT03928314 TERMINATED (No Reason Posted) Solid Tumor ORIC-101; Nab-paclitaxel Nab-paclitaxel, 100 mg/m^2; Relacorilant, 150 mg QD PHASE1 NCT02967159 COMPLETED (No Results Posted) Chronic Obstructive Pulmonary Disease (COPD) Asthma Abediterol; AZD7594; AZD7594/abediterol; AZD7594 and abediterol PHASE1 NCT03248713 TERMINATED (No Reason Posted) Nicotine Dependence Mifepristone; Placebo EARLY_PHASE1 NCT00522678 COMPLETED (No Results Posted) Asthma GW685698X; Placebo PHASE1 Mineralocorticoid receptor (MR) ~558 studies, https://clinicaltrials.gov/search?term=%E2%80%9CMineralocorticoid%20receptor%E2%80%9D&intr=drug Progesterone receptor (PR) ~426 studies, https://clinicaltrials.gov/search?term=%22Progesterone%20receptor%22&intr=drug Androgen receptor (AR) ~365 studies, https://clinicaltrials.gov/search?term=%22Androgen%20receptor%22&intr=drug Table 2 Summary of ongoing clinical trials of nuclear receptor-targeted drugs Target NCT number Study satus Conditions Agents Phases Retinoic acid receptor-α (RARα) NCT04793919 RECRUITING Acute Promyelocytic Leukemia Mylotarg; Arsenic Trioxide; All-trans retinoic acid (ATRA) PHASE2 NCT04113863 RECRUITING Breast Neoplasm Female ATRA; Anastrozole 1 mg PHASE2 NCT04460963 RECRUITING Acute Myeloid Leukemia Adrenomedullin NA NCT02688140 ACTIVE_NOT_RECRUITING Acute Promyelocytic Leukemia Arsenic trioxide; Idarubicin; Cytarabine; Tretinoin; Mitoxantrone; Mercaptopurine; Methotrexate PHASE3 Peroxisome proliferator-activated receptor-α (PPARα) NCT05781698 RECRUITING Inflammatory Bowel Diseases Mesalamine; Fenofibrate PHASE2 NCT05753267 RECRUITING Inflammatory Bowel Diseases Mesalamine; Fenofibrate PHASE2; PHASE3 NCT06125587 ENROLLING_BY_INVITATION Polycystic Ovary Syndrome Chiglitazar; Metformin PHASE2; PHASE3 NCT06155331 RECRUITING Breast Cancer Stage 2 and 3 Fenofibrate; Placebo; Doxorubicin; Cyclophosphamide PHASE4 NCT05542615 RECRUITING Liver Cirrhosis; Hepatitis C, Chronic; Epigenetic Disorder Prolonged-Release Pirfenidone PHASE2 Peroxisome proliferator-activated receptor-γ (PPAR-γ) NCT02391519 RECRUITING Pregnancy; IUGR; Preeclampsia NA NA NCT06125587 ENROLLING_BY_INVITATION Polycystic Ovary Syndrome Chiglitazar; Metformin PHASE2; PHASE3 NCT06010992 RECRUITING Diabetes Mellitus, Type 2 Nitazoxanide PHASE2 NCT05542615 RECRUITING Liver Cirrhosis Hepatitis C, Chronic Epigenetic Disorder Prolonged-Release Pirfenidone PHASE2 NCT03468556 NOT_YET_RECRUITING NASH - Nonalcoholic Steatohepatitis SNP-610; Placebo Oral Tablet PHASE2 NCT04114136 RECRUITING Melanoma;NSCLC; Hepatocellular Carcinoma; Urothelial Cancer; Gastric Adenocarcinoma; HNSCC;Esophageal Adenocarcinoma; Microsatellite Instability-High Solid Malignant Tumor Nivolumab or Pembrolizumab; Metformin; Rosiglitazone PHASE2 NCT05767671 RECRUITING Acute Respiratory Distress Syndrome;Ventilator Associated Pneumonia OTHER: Non-Bronchoscopic Mini Bronchoalveolar Lavage NA NCT06054607 RECRUITING Aerobic Endurance; Metabolism DIETARY_SUPPLEMENT: High-amylose maize starch+ acetate/butyrate; Low-amylose maize starch NA RAR-related orphan receptor-α (RORα) NCT04631341 NOT_YET_RECRUITING Cardiovascular Diseases DIETARY_SUPPLEMENT: Melatonin NA Steroid hormone receptor cnr14 (Sex-1) NCT06123650 RECRUITING Stroke, Acute; Dysphagia; Pneumonia DEVICE: Repetitve transcranial magnetic stimulation; Sham transcranial magnetic stimulation NA NCT06123650 RECRUITING Stroke, Acute; Dysphagia; Pneumonia DEVICE: Repetitve transcranial magnetic stimulation; Sham transcranial magnetic stimulation NA Farnesoid X receptor (FXR) NCT05718349 RECRUITING Cholestasis; Icterus; Cholangiocarcinoma; Pancreatic Neoplasms; Liver Metastasis Colon Cancer OTHER: Biospecimen sampling NA NCT03004118 ACTIVE_NOT_RECRUITING Functional Dyspepsia DIETARY_SUPPLEMENT: Nutridrink; DEVICE: High resolution manometry probe; DEVICE: perfusion catheter; Placebo Oral Tablet; Ursochol oral tablet; Duodenal fluid aspiration catheter; PROCEDURE: Duodenogastroscopy; Blood sample PHASE4 NCT04939051 RECRUITING Barrett Esophagus PROCEDURE: Biospecimen Collection; Esophageal Biopsy; Esophagogastroduodenoscopy; Liver Ultrasonographic Elastography; BIOLOGICAL: Obeticholic Acid; Placebo Administration; Questionnaire Administration PHASE2 NCT05740631 RECRUITING Healthy Ocaliva; Placebo NA NCT05639543 RECRUITING Alcohol Associated Hepatitis INT-787; Placebo PHASE2 Vitamin D receptor (VDR) NCT05802433 RECRUITING Vitamin D Deficiency DIETARY_SUPPLEMENT: Vitamin D3 supplement NA NCT05758259 ENROLLING_BY_INVITATION Acne Vulgaris; Vitamin D Combination oral and topical vitamin D; Oral placebo and topical cholecalciferol; Oral placebo and basic ingredient placebo topical vitamin D PHASE4 NCT03513770 RECRUITING Venous Distension Reflex; Blood Pressure OTHER: Wrist-to-elbow (W‒E) occlusion; ketorolac tromethamine; saline control EARLY_PHASE1 NCT02172651 RECRUITING Colon Cancer (Stage I-III); Stage IV Colon Cancer With Resectable Liver Metastases Vitamin D3; Placebo EARLY_PHASE1 NCT03467789 ACTIVE_NOT_RECRUITING Basal Cell Carcinoma; Basal Cell Nevus Syndrome Dietary Vitamin D3 pretreatment; RADIATION: Photodynamic therapy; Serum Maintenance Vitamin D3 PHASE1 NCT06209268 NOT_YET_RECRUITING Sepsis Paricalcitol injection; Placebo NA NCT05043116 RECRUITING Asthma in Children DIETARY_SUPPLEMENT: Cholecalciferol D3; Oral placebo suspension PHASE2 NCT01787409 RECRUITING Aggressive Non-Hodgkin Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-Cell Lymphoma; Chronic Lymphocytic Leukemia; Diffuse Large B-Cell Lymphoma; Enteropathy-Associated T-Cell Lymphoma; B-Cell Lymphoma; Nasal Type Extranodal NK/T-Cell Lymphoma; Mediastinal (Thymic) Large Hepatosplenic T-Cell Lymphoma; Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma; Peripheral T-Cell Lymphoma, Not Otherwise, Specified; Primary Cutaneous Anaplastic Large Cell Lymphoma;Refractory Anaplastic Large Cell Lymphoma; Small Lymphocytic Lymphoma; Subcutaneous Panniculitis-Like T-Cell Lymphoma DIETARY_SUPPLEMENT: Cholecalciferol NA NCT03004118 ACTIVE_NOT_RECRUITING Functional Dyspepsia DIETARY_SUPPLEMENT: Nutridrink; perfusion catheter; Placebo Oral Tablet; Ursochol oral tablet; Duodenal fluid aspiration catheter; PROCEDURE: Duodenogastroscopy; Blood sample PHASE4 NCT04677816 RECRUITING Triple Negative Breast Cancer; Vitamin D Deficiency; Invasive Breast Cancer Standard of Care Neoadjuvant Chemotherapy (NAC); DIETARY_SUPPLEMENT: Vitamin D3; Drug Diary PHASE2 NCT06279910 RECRUITING SARS-CoV 2 Pneumonia Calcifediol NA NCT03520790 ACTIVE_NOT_RECRUITING Pancreatic Cancer Gemcitabine; Nab-paclitaxel; Paricalcitol; Placebo PHASE1; PHASE2 NCT05981534 RECRUITING Vitamin D Deficiency; Sarcopenia; Knee Osteoarthritis Vitamin D; Placebo NA NCT05720273 RECRUITING Chronic Kidney Disease-Mineral and Bone Disorder Palicalcitol PHASE4 NCT06289257 NOT_YET_RECRUITING Endometriosis DIAGNOSTIC_TEST: Vitamin D level; Vitamin D receptor NA NCT06327581 RECRUITING Alopecia Areata Lactic Acid; vit D; Triamcinolone Acetonide; Saline NA NCT05839938 ENROLLING_BY_INVITATION Allergic Conjunctivitis Vitamin D; Placebo NA NCT05497596 RECRUITING Urticaria Vitamin D; Placebo NA NCT05633472 RECRUITING Postacute COVID-19 Syndromes Vitamin D; Placebo NA NCT05523986 RECRUITING Atopic Dermatitis Vitamin D; Placebo NA NCT03613116 ACTIVE_NOT_RECRUITING Vitamin D Deficiency; Cognitive Decline DIETARY_SUPPLEMENT: Vitamin D3 PHASE2 NCT02876211 RECRUITING Anemia Paricalcitol; Epoetin beta; Placebo PHASE4 Pregnane X receptor (PXR) NCT03004118 ACTIVE_NOT_RECRUITING Functional Dyspepsia DIETARY_SUPPLEMENT: Nutridrink; DEVICE: High resolution manometry probe; DEVICE: perfusion catheter; Placebo Oral Tablet; Ursochol oral tablet; DEVICE: Duodenal fluid aspiration catheter; PROCEDURE: Duodenogastroscopy; Blood sample PHASE4 Hepatocyte nuclear factor-4-α (HNF4α) NCT06092112 NOT_YET_RECRUITING Advanced Hepatocellular Carcinoma CD-801 EARLY_PHASE1 NCT06418659 NOT_YET_RECRUITING Advanced Hepatocellular Carcinoma CD-801 EARLY_PHASE1 Estrogen receptor-α (ERα) NCT02694809 RECRUITING Ductal Breast Carcinoma In Situ; Postmenopausal Conjugated Estrogens/Bazedoxifene; Laboratory Biomarker Analysis; Pharmacological Study; Placebo; Quality-of-Life Assessment; Questionnaire Administration PHASE2 NCT04174352 RECRUITING ERα+ Breast Cancer; ESR1 Gene Mutation Tamoxifen; DIAGNOSTIC_TEST: FES PET/CT EARLY_PHASE1 Glucocorticoid receptor (GR) NCT03674814 ACTIVE_NOT_RECRUITING Prostate Cancer Enzalutamide; Relacorilant PHASE1 NCT02788981 ACTIVE_NOT_RECRUITING Breast Cancer Mifepristone; Placebo; Nab-Paclitaxel PHASE2 NCT04452500 RECRUITING PTSD CORT108297; Placebo PHASE2 NCT05726292 RECRUITING Prostate Cancer; Prostate Adenocarcinoma Relacorilant; Enzalutamide; Placebo (Sugar Pill); Androgen Deprivation Therapy; Radical Prostatectomy PHASE2 NCT04601038 RECRUITING Mild Cognitive Impairment; Alzheimer Disease; Memory Impairment CORT108297; Placebo PHASE2 NCT04308590 ACTIVE_NOT_RECRUITING Hypercortisolism Relacorilant; Placebo PHASE3 Mineralocorticoid receptor (MR) ~558 studies, https://clinicaltrials.gov/search?term=%E2%80%9CMineralocorticoid%20receptor%E2%80%9D&intr=drug Progesterone receptor (PR) ~426 studies, https://clinicaltrials.gov/search?term=%22Progesterone%20receptor%22&intr=drug Androgen receptor (AR) ~365 studies, https://clinicaltrials.gov/search?term=%22Androgen%20receptor%22&intr=drug

Targeting nuclear receptors in cancer

NRs, especially those that bind to three steroid hormones, namely, estrogen, progesterone and androgen, play a significant role in the development of human malignancies, particularly breast cancer, 355 , 356 ovarian cancer 357 and prostate cancer. 358 In recent years, NR-targeted drugs have attracted widespread attention as novel therapeutic strategies 359 – 361 that play a significant role in inhibiting the growth and progression of many types of cancer.

Within the nuclear receptor superfamily, ERs were the first nuclear receptors to be described. Breast cancer is the most common cancer in women, with ER + breast cancer accounting for approximately 75% of all cases. Numerous studies have confirmed that ERα plays a causative role in carcinogenesis. As a result, an increasing number of ERα-based targeted medicines have entered preclinical and clinical trials (Table 1 ), and some have even received FDA approval. This includes directly antagonizing the estrogen receptor via SERMs and selective estrogen receptor degraders (SERDs). These drugs include ER antagonists, selective ER modulators and aromatase inhibitors. 362 ER antagonists competitively inhibit the ER, whereas selective ER modulators function as partial agonists or antagonists on the basis of their tissue affinity. Aromatase inhibitors decrease estrogen production by blocking aromatase in tissues such as the ovaries and adipose tissue. 363 , 364 Tamoxifen is the most widely used antiestrogen for hormone-dependent breast cancer and is indicated for various treatment settings. Evidence shows that patients with estrogen receptor-positive tumors are more likely to benefit from tamoxifen. FDA-approved treatments include treating breast cancer in both females and males, providing adjuvant therapy after surgery and radiation, treating female patients with ductal carcinoma in situ (DCIS) postsurgery and radiation to lower the risk of invasive breast cancer and reduce the risk of breast cancer in certain high-risk patients. 365 , 366 In addition to tamoxifen, many other SERMs, including raloxifene, lasofoxifene, bazedoxifene and fulvestrant, have been developed and used for breast cancer treatment. 363 These drugs have also been used to treat other tumors with high estrogen expression. In addition to hormone-dependent breast cancer, antiestrogen medications such as tamoxifen and aromatase inhibitors have shown efficacy in managing conditions such as endometrial cancer and certain types of ovarian cancer. 367 , 368 Although estrogen levels are low in prostate tissue, ER expression has been detected in some prostate cancer patients. 369 ER activation is believed to be associated with the proliferation and metastasis of prostate cancer cells. 370 Thus, antiestrogen therapy targeting the ER has also been proposed as a new treatment strategy for prostate cancer. For example, in males with advanced prostate cancer, an ERα agonist, GTx-758, has been shown to lower testosterone with fewer side effects associated with androgen-deprivation therapy. 371

Bidedoxifene is the most recent generation of SERMs. Fanning and colleagues demonstrated that bazedoxifene works in concert with palbociclib, a CDK4/6b inhibitor, and is more effective than tamoxifen against specific ERα mutants, such as Y537S and D538G. A phase II clinical trial in patients with ductal carcinoma in situ [ NCT02694809 ] and a phase I/II clinical trial on bazedoxifene in combination with palbociclib in hormone receptor-positive breast cancer [ NCT02448771 ] are two examples of the numerous clinical trials that have examined bazedoxifene across a variety of cancer types. Degradation of this receptor by SERDs is another tactic to target ERs. Fulvestrant is the most researched SERD, and its clinical application has been growing. Clinical trials have combined fulvestrant with CDK4/6 inhibitors, such as ribociclib in men and postmenopausal women with advanced breast cancer [ NCT02422615 ] and palbociclib in hormone receptor+HER2-metastasized breast cancer after endocrine failure [ NCT01942135 ], as well as phosphatidylinositol 3-kinasitol kinase (PI3K)/AKT/mTOR pathway inhibitors, such as pictilisib, in advanced or metastatic breast cancer in participants resistant to aromatase inhibitor therapy [ NCT01437566 ].

The abnormal expression of AR in prostate cancer cells makes anti-AR drugs a logical treatment strategy. 372 These drugs inhibit AR function through various mechanisms, reducing androgen stimulation of tumor cells. Among the most common anti-AR agents are AR antagonists such as abiraterone and enzalutamide. These drugs competitively bind to the AR, preventing androgen attachment and inhibiting receptor activity. Abiraterone has been shown to prolong survival in patients with metastatic castration-resistant prostate cancer (mCRPC). 373 In the context of metastatic castration-sensitive prostate cancer (mCSPC), a combination treatment involving abiraterone, prednisone and docetaxel has favorable effects. 374 Furthermore, for metastasis-free survival, combining enzalutamide with leuprolide has shown superior outcomes compared with leuprolide alone in high-risk patients with biochemical recurrence. Additionally, enzalutamide monotherapy has outperformed leuprolide monotherapy. 36 The prostate cancer community has recently focused much attention on a number of newly created AR proteolysis-targeting chimeras (PROTACs), which were created as SARDs. ARV-110 [ NCT03888612 ], the first AR PROTAC to reach clinical trials, is now being used in patients with metastatic CRPC and is undergoing a phase I/II clinical trial. In contrast to clinically licensed AR antagonists, ARD-61, a novel AR PROTAC, has been shown to efficiently promote on-target AR degradation, elicit more potent antiproliferative and proapoptotic effects, and reduce downstream AR target gene expression in prostate cancer cells. The most effective AR PROTACs may eventually be utilized extensively in cancer patients, and we expect more advancements to the clinical trial stage.

Additionally, RARs and their heterodimer partners, such as PPARs and RXR, which are involved in vitamin A metabolism, cell differentiation and immune regulation, also have therapeutic potential. 375 , 376 Aberrant RXR signaling can promote cancer development by disrupting normal cellular homeostasis and enhancing oncogenic processes. RXR agonists have shown potential in treating various advanced cancers in clinical trials. IRX4204, in combination with erlotinib, is under investigation for previously treated advanced non-small cell lung cancer (NSCLC) [ NCT02991651 ]. NRX194204 is being studied for its efficacy in castration- and taxane-resistant prostate cancer [ NCT01540071 ] and advanced NSCLC [ NCT00964132 ]. Additionally, bexarotene is being evaluated for the treatment of metastatic breast cancer and relapsed or refractory cutaneous T-cell lymphoma in patients with stage III or IV disease [ NCT00003752 , NCT00514293 , NCT01134341 , NCT00316030 ]. These studies underscore the therapeutic potential of RXR agonists in managing resistant and advanced malignancies. PPAR agonists have shown promising antitumor effects across a range of cancers, either as standalone treatments or in combination therapies. Troglitazone has shown efficacy in prostate cancer and liposarcoma [ NCT00003058 ], whereas pioglitazone is being studied for advanced solid tumors [ NCT02133625 ], pancreatic cancer [ NCT01838317 ], and thyroid cancer [ NCT01655719 ], often with chemotherapy. Inolitazone combined with paclitaxel is under investigation for advanced anaplastic thyroid cancer [ NCT02152137 ]. Rosiglitazone is being explored for the treatment of liposarcoma [ NCT00004180 ], metastatic thyroid cancer [ NCT00098852 ], and androgen-dependent prostate cancer [ NCT00182052 ]. These trials demonstrate the therapeutic potential of PPAR agonists in treating challenging malignancies. Retinoic acid, a natural RAR agonist, regulates the expression of genes related to cell growth. Studies suggest that RAR/RXR agonists may have antitumor effects on prostate cancer. For example, the RAR agonist adapalene has been shown to induce a tumor-suppressive senescence-associated secretory phenotype (SASP) in prostate cancer cells. In combination with docetaxel, adapalene enhanced tumor suppression and improved natural killer (NK) cell-mediated clearance in preclinical models. This approach also increased the efficacy of NK cell infusion in mice with human prostate cancer, leading to greater tumor suppression. 377

REV-ERBs, including REV-ERBα (NR1D1) and REV-ERBβ (NR1D2), are key regulators of the circadian clock. Notably, many tumor types exhibit elevated expression of REV-ERBβ, regardless of ERBB2 or ER status, whereas nonmalignant mammary epithelial cells primarily express REV-ERBα. High levels of REV-ERBβ in cancer cells have been linked to reduced sensitivity to chloroquine via the modulation of autophagy, suggesting a role in therapy resistance. REV-ERB agonists, such as SR9009 and SR9011, selectively target cancer cells and oncogene-induced senescent cells, such as melanocytic naevi, without impacting normal cell viability. These agonists have shown promising anticancer effects, including reduced glioblastoma growth and improved survival in mice, without causing significant toxicity. 378

Targeting nuclear receptors in metabolic-related diseases

Metabolic diseases such as nonalcoholic fatty liver disease (NAFLD), obesity, type 2 diabetes and atherosclerosis represent a growing global health burden. 379 , 380 These conditions are frequently associated with dysregulated lipid or glucose metabolism. 381 , 382 NRs play crucial roles in maintaining metabolic homeostasis by controlling the expression of genes involved in lipid, glucose and energy metabolism. Among NRs, PPARs, farnesoid X receptor (FXR), liver X receptor (LXR) and pregnane X receptor (PXR) have been identified as promising therapeutic targets. Drugs that modulate these receptors, such as PPAR agonists and FXR agonists, have demonstrated promising activity in clinical trials for the treatment of metabolic disorders, particularly NAFLD. Here, we explore current and emerging therapies that target these receptors.

One of the most well-known nuclear receptors is the PPAR family. PPAR agonists, such as pioglitazone and rosiglitazone, can increase insulin sensitivity in individuals with T2D. By activating PPARγ, these drugs enhance glucose uptake and lipid storage, which helps to lower blood sugar levels and improve metabolic control. However, these drugs are associated with certain risks, such as weight gain and fluid retention, necessitating careful patient management. PPARα agonists, such as fibrates, have been used clinically for 35 years to regulate blood lipids and prevent atherosclerosis. 383 Pemafibrate was introduced in Japan in June 2018 and has since been demonstrated to be effective in inhibiting VLDL secretion and enhancing triglyceride (TG) clearance by activating LPL. 384 In mice fed a high-fat diet, it suppressed postprandial hyperlipidemia by downregulating the mRNA expression of the intestinal cholesterol transporter NPC1L1 and upregulating genes involved in β-oxidation to inhibit VLDL secretion from the liver. In a 4-week trial with dyslipidemic patients (0.4 mg/day), pemafibrate significantly reduced fasting and nonfasting serum TG, RemL-C, and apo B-48 levels, with a marked reduction in the postprandial TG AUC, indicating improved postprandial hypertriglyceridemia. 385 Similar results were observed in diabetic patients treated with pemafibrate. 386 PPARγ and PPARδ regulate energy utilization and insulin sensitivity in skeletal muscle and adipose tissue. High insulin levels accelerate the development of NAFLD through a PPARγ-dependent pathway. 387 PPARγ agonists, thiazolidinediones, have been used as insulin sensitizers in diabetic patients. 388 PPARδ agonists improved the pathological manifestations of nonalcoholic steatohepatitis (NASH) without affecting body weight. The dual PPARα/δ agonist elafibranor (GFT505) improved glycemic and lipid metabolism in NASH patients in a phase II clinical trial, reduced liver inflammation and did not exacerbate fibrosis, demonstrating good tolerability. Phase III clinical trials targeting NASH patients [ NCT02704403 ] are ongoing. A phase II clinical trial of the dual PPARα/γ agonist Saroglitazar [ NCT03061721 ] in NASH patients was completed in April 2020. Midterm reports revealed not only regression of NASH tissue lesions but also decreased serum ALT levels, indicating improved liver function. The Indian pharmaceutical company Zydus Cadila has submitted a marketing application for this drug.

Another good NR drug target is FXR, which regulates bile acid metabolism and lipid homeostasis. FXR activation improves lipid metabolism and reduces liver inflammation, offering a new avenue for managing metabolic liver disorders. 389 – 391 Obeticholic acid, an FXR agonist also known as INT-747, is approved for treating NAFLD and NASH 392 [ NCT02548351 ]. Owing to its ability to lower ALP levels and combat cholestasis and fibrosis, obeticholic acid (Ocaliva) was initially approved as a treatment for primary biliary cholangitis. In a phase III clinical trial for NASH [ NCT02548351 ], obeticholic acid improved liver function and reduced tissue pathology, although it exhibited some side effects, such as pruritus and increased low-density lipoprotein levels. Given that pruritus can be managed symptomatically and that dyslipidemia can be addressed by the concomitant use of statins, the United States Food and Drug Administration has approved obeticholic acid as the primary treatment for NASH. Several other FXR agonists with diverse physicochemical characteristics, including bile acid derivatives, nonbile acid-derived steroidal FXR agonists, nonsteroidal FXR agonists and partial FXR agonists, are also progressing through advanced stages of clinical development. The noncarboxylic acid steroidal FXR agonist EDP-305 has been shown to modulate many pathways that trigger antilipogenic, anti-inflammatory and antifibrotic gene signatures. This resulted in hepatoprotective and antisteatotic effects in a mouse model of NASH. 393 Patients with intestinal failure require more complicated care when they have parenteral nutrition (PN)-associated cholestasis (PNAC). By restoring hepatic FXR signaling, GW4064 protected animals against PNAC by increasing the expression of sterol and phospholipid transporters and canalicular bile and suppressing the recruitment and activation of macrophages. These findings suggest that increasing FXR activity could be used as a therapeutic approach to treat or prevent PNAC. 394

In addition to PPAR and FXR, LXR is involved in cholesterol metabolism and can be targeted for atherosclerosis treatment. LXR agonists have been shown to increase cholesterol efflux and reduce the development of atherosclerotic plaques in preclinical models. 395 However, treating patients with medications that increase cholesterol is not a practical option for metabolic illnesses; instead, methods for separating the advantageous effects of LXR ligands from unfavorable side effects must be investigated. Taken together, these examples highlight the growing potential of NR-targeted drugs in addressing the underlying causes of metabolic disorders, offering more precise and effective treatments than traditional approaches do.

Targeting nuclear receptors in cardiovascular diseases

The targeting of NRs for the treatment of cardiovascular diseases has gained significant attention because of the pivotal role these receptors play in regulating the expression of genes involved in metabolic, inflammatory and lipid processes. 361 , 396 – 398 Nuclear receptors, such as PPARs, LXR and FXR, are key regulators of lipid metabolism, glucose homeostasis and inflammation, all of which are critical factors in the development of cardiovascular diseases. By modulating these receptors, it is possible to control pathological processes such as atherosclerosis, hypertension and other cardiovascular disorders.

The NRs RORα and REV-ERBα are key components of the circadian system and regulate biological rhythms, glucose metabolism, lipid metabolism, vascular inflammation and fibrinolysis. 399 RORα is instrumental in endothelial progenitor cell (EPC) differentiation and promotes angiogenesis, tissue repair and vascular stability by inducing erythropoietin production and activating AMPK. 400 RORα mediates the protective effects of melatonin, including its anti-inflammatory, antioxidant and antiapoptotic effects, making it a potential therapeutic target for atherosclerosis and endothelial dysfunction. 401 , 402 In hypertensive rats, melatonin altered clock gene expression patterns, maintaining high levels of REV-ERBα mRNA, which regulated blood pressure rhythms. This effect is linked to melatonin receptor activity and may involve posttranslational mechanisms. 403 Increased RORα expression, which is stimulated by melatonin and the sympathetic nervous system, also protects against programmed hypertension. A number of small-molecule agonists for RORα and REV-ERBα, such as the pharmacological agents SR9009 and GSK4112 for REV-ERBα, have been developed 404 and are available for use in cellular and animal experiments, but prospective studies on the impact of stable circadian rhythms on CHD and heart failure are still limited. 405 , 406 When considered collectively, the bulk of current research points to considerable clinical value and therapeutic potential for medications that target RORα and REV-ERBα to treat hypertension and atherosclerosis.

Several studies have highlighted the function of RXRs in cardiovascular disease. Treatment with 9cRA or the synthetic RXR agonist LGD1069 (bexarotene) has been shown to reduce oxidative stress-induced cell damage and preserve the mitochondrial membrane potential. 407 In heart failure, oxidative stress activates angiotensin-II (AngII), leading to harmful cardiac remodeling and dysfunction. Bexarotene treatment of cultured rat aortic smooth muscle cells inhibited AngII-driven inflammation and p38 MAPK activation, suggesting that RXR activation has protective effects on cardiac disease. 408 ERRα and ERRγ are essential for normal postnatal cardiovascular function, whereas ERRβ supports maximal ATP generation in contracting cardiomyocytes. ERR agonists help maintain oxidative metabolism, which protects the heart against pressure overload-induced heart failure (HF) in vivo. Using a structure-based design, Xu and colleagues synthesized two pan-ERR agonists, SLU-PP-332 and SLU-PP-915, each of which significantly improved the ejection fraction, reduced fibrosis and enhanced survival in models of pressure overload-induced HF without affecting cardiac hypertrophy. 409 Targeting other nuclear receptors, such as RARs, PPARs, and LXRs, has also shown promise for ameliorating cardiovascular disease. 410 , 411 These findings provide strong pharmacological evidence supporting the potential of targeting NRs for cardiovascular disease management.

Targeting nuclear receptors in central nervous system disorders

Alzheimer’s disease (AD), PD, Huntington’s disease (HD), multiple sclerosis (MS), cerebral ischemia, stroke and other conditions are common central nervous system disorders that currently affect approximately one hundred million people worldwide. Compelling evidence suggests that nuclear receptors are important in these disorders and that targeting these receptors has significant therapeutic potential. 353

Liver X receptor LXRs are key regulators of cholesterol trafficking in the central nervous system (CNS), working with ApoE to facilitate cholesterol recycling and efflux, which are essential for maintaining CNS homeostasis. Dysregulation of LXR signaling is linked to neurodegenerative diseases such as AD, PD and Niemann‒Pick type C disease. LXR activation offers therapeutic potential by modulating neuroinflammation in CNS disorders. In AD models, LXR agonists such as T0901317 reduce inflammation associated with amyloid-beta (Aβ) deposition and tau tangles by suppressing microglial activation and the expression of inflammatory markers such as iNOS, COX-2, and NF-κB. Similar effects are observed in PD models, where T0901317 decreases iNOS and COX-2 levels. In Niemann–Pick type C disease, LXR activation promotes cholesterol clearance, reduces cerebellar inflammation, and extends lifespan. LXRs also enhance blood‒brain barrier (BBB) integrity by increasing the expression of ABC transporters such as ABCB1, which prevents toxin entry into the brain. Natural LXR agonists (e.g., oxysterols) and RXR activation (e.g., with bexarotene) improve BBB function in coculture models, whereas LXR agonists support tissue regeneration in ischemic stroke by stabilizing the BBB and reducing inflammatory cytokines. Although preclinical results are promising, the clinical translation of LXR agonists is hindered by side effects, including elevated triglycerides and LDL cholesterol. 284 Efforts to mitigate these issues include the development of selective LXRβ agonists, regional drug delivery, and the targeting of specific downstream pathways, making LXRs promising therapeutic targets for CNS diseases.

PPARs, particularly PPARγ, play pivotal roles in neuroprotection by regulating neuroinflammation, mitochondrial function, and antioxidant defenses. It is expressed in various CNS cell types, including neurons, astrocytes, oligodendrocytes, and microglia. Dysregulation of PPARs is associated with neurodegenerative diseases characterized by inflammation, such as AD and amyotrophic lateral sclerosis (ALS). PPARγ agonists, including endogenous ligands such as OA and synthetic compounds such as rosiglitazone and pioglitazone, have shown promise in preclinical models because they reduce inflammatory cytokines, increase IL-10 levels, and enhance mitochondrial function in conditions such as stroke, ischemia, and traumatic brain injury. Moreover, PPARγ activation has exhibited potential benefits in neuropsychiatric disorders (e.g., depression, anxiety, and mood disorders) and neurodegenerative diseases, with ongoing clinical trials exploring its applications in AD, PD, MS, and bipolar disorder 412 [ NCT00982202 , NCT00736996 , NCT00265148 , NCT00733785 , NCT00688207 , NCT01280123 ]. However, mixed clinical outcomes highlight gaps in understanding the mechanisms of PPARγ within the CNS. 413 Further research aimed at optimizing PPARγ activity may unlock its full therapeutic potential for treating neurodegenerative and neuropsychiatric conditions.

The GR also plays a critical role in neuroinflammation, neuroprotection, and brain homeostasis. Its anti-inflammatory effects in the brain are mediated through interactions with AP-1 and NF-κB, limiting their transcriptional activity. 414 GR also regulates brain-derived neurotrophic factor (BDNF), promotes neurogenesis, neuronal survival, and synaptic plasticity, and contributes to memory, aging, and behavior. Additionally, GR supports BBB integrity by upregulating tight junction proteins and establishing metabolic barriers to xenobiotics. 415 , 416 GR dysfunction has been implicated in various neuropathologies, including AD, HD and epilepsy. Abnormal GR expression in AD is correlated with hippocampal overexpression, impaired cortisol feedback, and memory deficits. 417 Similarly, GR overexpression in epilepsy has been associated with reactive gliosis and coregulation with PXR in epileptic brain endothelial cells. GR dysregulation also affects HD-related changes, such as increased cortisol secretion and muscular atrophy, alongside reduced GR expression in the hypothalamic and pituitary regions. GR abnormalities also underlie mood disorders such as depression and anxiety, as dysfunction in GR and MR signaling leads to maladaptive stress responses, dendritic retraction, and impaired serotonin activity. 418 , 419 GR dysregulation in the prefrontal cortex and hippocampus has been linked to anxiety and depression-like behaviors in animal models. Pharmacological modulation of the GR provides therapeutic opportunities. GR agonists, such as dexamethasone and methylprednisolone, are widely used to treat neurological conditions such as gliomas, MS, and traumatic brain injuries. Dexamethasone reduces edema, prevents cerebrovascular leakage, and upregulates tight junction proteins at the BBB. 420 , 421 Methylprednisolone improves memory and long-term potentiation at low doses but has dose-dependent effects, with high doses alleviating motor deficits in MS models but not cognition. 422 , 423 GR antagonists, such as mifepristone and relacorilant, have shown efficacy in treating mood disorders, neurodegenerative conditions, and PTSD. Mifepristone restores serotonin signaling and alleviates depression-like behaviors, whereas relacorilant is undergoing phase II and III trials for conditions such as Cushing syndrome and prostate cancer 424 , 425 [NCT036748142019, NCT036971092019]. These findings underscore the potential of targeting GRs in a range of CNS disorders.

Estrogens and their receptors play critical roles in neuroprotection and the regulation of inflammatory and neurodegenerative processes in the CNS. Owing to their antiapoptotic, antioxidative, and anti-inflammatory properties, estrogens provide early protection against ischemic injury. ERα and ERβ agonists, such as diarylpropionitrile (DPN), have demonstrated neuroprotective effects by mitigating damage in ischemic models, including the caudate nucleus and CA1 region of ovariectomized mice and the striatum of male mice. The membrane receptor GPER-1 also contributes to ischemic protection, with its agonist G1 offering estrogen-like neuroprotection, particularly in males, as suggested by sex-dependent differences in GPER-1 expression. In addition to estrogens, NRs such as Nr4a2 and bile acid receptors play vital roles in alleviating neuroinflammation and neuropathic pain. Nr4a2 helps regulate depressive-like behaviors by preventing structural and functional damage to anterior cingulate cortex (ACC) microglia and excitatory neurons during chronic neuroinflammation. 426 Its upregulation through the dopaminergic agonist pramipexole has demonstrated neuroprotective effects on dopaminergic neurons in Parkinson’s disease. 427 Similarly, bile acids activate TGR5 and FXR, alleviating mechanical hyperalgesia by reducing glial activation and neuronal sensitization in the spinal dorsal horn. The presence of bile acid synthesis enzymes in spinal astrocytes suggests an endogenous mechanism for decreasing nociceptive neuron transmission and mechanical hypersensitivity, emphasizing bile acid receptors as promising targets for neuropathic pain relief. 428 In MS, Th17-driven inflammation is aggravated by RORγt overexpression, which promotes Th17 cell differentiation. By suppressing RORγt, vitamin A has shown therapeutic potential for MS 429 [ NCT01225289 ]. Collectively, these findings highlight the diverse and pivotal roles of estrogens and nuclear receptors in neuroprotection, inflammation regulation, and the development of innovative therapeutic strategies.

Targeting nuclear receptors in infectious diseases

In recent decades, global spending on infectious diseases has increased significantly, with treatment costs rising faster than those for other diseases. Infectious diseases caused by bacteria, viruses, fungi, and parasites include common conditions such as pneumonia, influenza, gastroenteritis, hepatitis, malaria, and dengue fever, as well as diseases such as HIV/AIDS, tuberculosis, and COVID-19. NRs play a key role in regulating immune responses by modulating genes involved in inflammation, pathogen defense, and immune cell function, thus influencing the outcome of both bacterial and viral infections. Given the increasingly appreciated roles of NRs in the context of infections, targeting NRs may provide a new, largely unexplored area for infectious disease treatment. 430

The role of FXR extends to hepatitis C virus (HCV) infection, where it, along with other NRs, such as HNF4α, PPARα, and PXR, reprograms hepatocyte metabolism, influencing glycolysis, ketogenesis, and drug metabolism. 431 The targeting of FXR or PPARα in HCV infection has shown complex antiviral effects, with receptor inhibition reducing viral replication by reversing HCV-induced metabolic shifts. Furthermore, FXR agonists such as GW4064 have demonstrated potential in alleviating inflammation and preserving intestinal barrier function in experimental colitis, primarily through the modulation of NF-κB signaling. 432 , 433 In addition, GW4064 has been reported to downregulate scavenger receptors via FXR and indirectly inhibits HCV entry into cells. 434

In addition to their roles in viral infections, NRs are essential in bacterial infection. For example, PPARγ signaling is crucial for resolving Staphylococcus aureus (MRSA) infections and improving outcomes in sepsis models by modulating inflammation. 435 PPARγ agonists such as pioglitazone have been shown to restore mitochondrial function and reduce oxidative stress in macrophages, highlighting their potential in treating inflammatory and infectious diseases. 436 LXRs are involved in macrophage phagocytic responses, particularly during Salmonella Typhimurium infections. 437 In a mouse model, LXR agonist treatment ameliorated clinical signs of Salmonella infection in a CD38-dependent manner. 438 Recent transcriptomic studies investigating susceptibility to dengue virus in a Cuban cohort of African ancestry revealed increased gene expression of RXR in individuals who were more resistant to infection and suggested a protective role for LXR/RXR against dengue virus. 439 In the case of tuberculosis (TB), NRs such as Nur77 and Nor1 are upregulated in response to Mycobacterium tuberculosis infection. Interestingly, the first-line TB drug rifampicin activates PXR, which can impair its effectiveness in infected macrophages, underscoring the complex interactions between NRs and drug efficacy. 440 , 441 Rifampicin, a first-line anti-tuberculosis (TB) drug, is a potent activator of PXRs, which in turn compromises the effect of rifampicin in M. tuberculosis -infected human macrophages. 442

NRs also influence fungal infections, with PPARγ playing a central role in defending against Candida albicans in the gastrointestinal tract. PPARγ ligands reduce fungal colonization through a dectin-1-dependent mechanism. Sepsis models have revealed a critical role for PPARγ in controlling inflammation and improving overall disease outcomes. PPARγ gene expression was downregulated in freshly isolated peripheral blood mononuclear cells (PBMCs) from human sepsis patients as well as in the lungs in a murine sepsis model. 443 Treatment with PPARγ agonists improved sepsis outcomes, decreased proinflammatory cytokine levels, increased IL-10 levels, and improved mouse survival. 444 Other PPAR isoforms have also been linked to decreased severity of sepsis through the downregulation of inflammation. In a cecal ligation and puncture rat sepsis model, treatment with a PPARβ/δ agonist inhibited signal transducer and activator of transcription 3 (STAT3) activation in AMs, reduced the inflammatory response, and prolonged rat survival. 445 , 446

Parasitic worms are among the global health threats to billions of humans worldwide. 447 , 448 Although several anthelmintic drugs, including benzimidazole, levamisole/morantel and ivermectin, have been used to treat these parasites, resistance frequently occurs. Therefore, identifying novel therapeutic targets in parasitic diseases is urgently needed. Nuclear receptors, which are well-known therapeutic targets in humans, are currently being investigated in parasitic worms because of their widespread distribution and important functions in controlling transcriptional networks involved in metabolism and development. 449 Among them, DAF-12 is a nuclear receptor that is necessary for the typical development of nematodes, including the crucial infectious stage. In free-living nematodes such as C. elegans , a lack of DAF-12 ligands (such as dafachronic acid (DA)) under stress conditions promotes entry into the L3d (dauer diapause) state, whereas supplementation with DAF-12 ligands in prosperous environments leads to their exit from L3d and the beginning of reproductive development. 450 In contrast, in parasitic nematodes such as S. stercoralis, the absence of a DAF-12 ligand leads to an L3d ortholog stage, termed the infectious L3 (iL3) stage, during preinfection, whereas the presence of a DAF-12 ligand in the definitive host can resume reproductive development. 451

The mechanism underlying DAF-12-mediated cell fate decisions is similar to that of other nuclear receptors. Briefly, under favorable conditions or in a host-specific environment, DAF-12 binds with its ligand and is thus activated, which induces the transcription of target genes that facilitate metabolism and development. In contrast, under stress conditions, DAF-12 is inactive without ligand binding, resulting in transcriptional repression and subsequent development arrest and infection. Thus, strategies targeting DAF-12 or its ligands have potential for the treatment of parasitic diseases. In addition to exogenous DA, endogenous Δ7-DA was recently reported as a novel ligand of DAF-12 in S. stercoralis. The abundance of Δ7-DA is regulated by several enzymes, including DAF-36, DHS-16, and DAF-9, which govern the on/off switch of the reproduction, infection and development processes in this parasitic nematode. 452 In addition to receptors and ligands, other components, such as cofactors, can also be potential targets for the manipulation of the life cycle of parasitic nematodes. For example, DAF-12 interacting protein-1 (DIP-1) was recently identified as a coactivator of DAF-12, which is indispensable for the ligand-activated transcriptional activity of DAF-12 in Strongyloides spp. 453 Together, this evidence suggests that the nuclear receptor DAF-12 is a promising target for the treatment of parasitic diseases.

Targeting nuclear receptors in reproductive diseases

Polycystic ovary syndrome (PCOS) is a type of reproductive disease that affects 5–18% of women worldwide who are of reproductive age. 454 Interestingly, patients with PCOS are frequently associated with metabolic syndrome, such as obesity, dyslipidemia, impaired glucose tolerance or increased fasting insulin, 455 which is closely linked to an abnormal gut microbiome. A recent study revealed that PCOS can be induced by alterations in the gut microbiome via the activation of the nuclear receptor FXR. 456 Mechanistically, agmatine produced by B. vulgatus can activate FXR, which in turn prevents L cells from secreting glucagon-like peptide-1 (GLP-1), suggesting that FXR is a possible therapeutic target for the treatment of PCOS. 456 Moreover, PPAR is a large nuclear receptor superfamily related to energy metabolism and is thus involved in the progression of PCOS. In fact, all three PPAR family members, including PPARα, PPARβ/δ and PPARγ, play critical roles in PCOS via multiple mechanisms, such as the regulation of lipogenesis; glucose homeostasis; and fatty acid oxidation, synthesis and storage. 457 Given the important function of PPARs in PCOS pathogenesis, modulating the activity of PPARs profoundly affects the development of PCOS. For example, the activation of PPARγ by a polyphenolic compound, sinapic acid, was shown to ameliorate metabolic dysfunction and attenuate PCOS phenotypes in rats. 458 Another study focusing on the downstream mechanism underlying PPAR-mediated alleviation of PCOS indicated that PPARα can bind to the promoter of FADS2, a ferroptosis-related gene, thus increasing FADS2 transcription. This event inhibits ferroptosis of granulosa cells in a dehydroepiandrosterone (DHEA)-induced PCOS mouse model, suggesting that PPARα alleviates PCOS by protecting granulosa cells from ferroptosis. 459

Uterine leiomyomas, another name for uterine fibroids, are benign tumors of the fibrotic smooth muscle in the reproductive system. The ovarian steroid hormone estrogen, as well as its receptor ER, are involved in this disease. 460 In addition, other nuclear receptors, such as the NR4A protein family, may also participate in the progression of uterine fibroids. 461 NR4A restricts the proliferation of primary leiomyoma smooth muscle cells by modeling the extracellular matrix, whereas low expression of NR4A contributes to the pathogenesis of uterine fibroids. Moreover, leuprolide acetate, a GnRH analog used to treat uterine fibroids, can restore the expression of NR4A1 and NR4A3 in clinical samples, suggesting that these two NR4A family members might be additional targets of leuprolide acetate in addition to sex steroid receptors.

Targeting nuclear receptors in renal diseases

While NRs are intimately involved in proper kidney function, they are also implicated in a variety of renal diseases, such as diabetes, acute kidney injury, and other conditions, such as aging. In the last 10 years, our understanding of renal disease etiology and progression has been greatly shaped by knowledge regarding how NRs are dysregulated in these conditions. Importantly, NRs have also become attractive therapeutic targets for the attenuation of renal diseases, and their modulation for this purpose has been the subject of intense investigation. Here, we review the roles of six key renal NRs, including PPAR, ERR, FXR, ER, LXR, and VDR, in health and disease, with an emphasis on recent findings over the last decade.

PPARs are involved in various renal diseases, both acute and chronic. PPARα-null mice treated with streptozotocin (STZ) exhibit accelerated diabetic nephropathy, including worsened albuminuria, glomerular sclerosis, mesangial matrix expansion, collagen deposition, and macrophage infiltration. PPARα agonists have been studied as potential treatments for diabetic nephropathy (DN) in rodents, with evidence supporting their renoprotective effects. Recent research by Chung et al.demonstrated that impairment of PPARα and fatty acid oxidation exacerbates kidney fibrosis during aging, with reduced PPARα expression and lipid accumulation in tubular cells. 462 PPARα-null mice also exhibit more severe renal aging and fibrosis. Jao et al.reported that ATF6 downregulates PPARα transcription, leading to decreased fatty acid oxidation and increased lipotoxicity in proximal tubule cells, whereas ATF6-deficient mice exhibit increased PPARα expression and decreased lipid accumulation. 463 In addition to PPARα, PPARγ has also been studied in DN, with evidence suggesting that its activity is suppressed in this disease. Unlike other PPAR family members, PPARβ/δ is ubiquitously expressed in both cortical and medullary cells. Recent studies have highlighted a potential role for PPARβ/δ in renal homeostasis. For example, Kirkby et al. demonstrated that activation of renal PPARβ/δ by endogenous prostacyclin induces vasodilation and improves blood flow, a process regulated by cyclooxygenase-2 (COX-2). 464 This COX-2/prostacyclin/PPARβ/δ axis offers new insights into kidney vascular physiology and therapeutic possibilities. Additionally, activation of PPARβ/δ has been shown to improve renal dysfunction in a lupus mouse model by lowering blood pressure, reducing renal hypertrophy, decreasing albuminuria, and preventing renal injury. 465

Additionally, other nuclear receptors play key roles in kidney health. ERRs are crucial regulators in the kidneys, where they help maintain metabolic balance, regulate monovalent cation homeostasis, and control blood pressure. 466 The importance of ERRs is further highlighted by the fact that the deletion of ERRγ leads to significant mitochondrial dysfunction and progressive renal failure. 467 For example, ERRα has been shown to protect against AKI in tubular epithelial cells, particularly in cases of cisplatin-induced AKI in mice. 468 Compared with those in wild-type mice, in ERRα-null mice subjected to cisplatin treatment, tubular injury, a reduced mitochondrial content, abnormal mitochondrial morphology, and increased oxidative stress were observed. A recent study demonstrated that Nr4a1 was upregulated in the kidneys of mice with unilateral ureteral obstruction (UUO), and its expression was positively correlated with the degree of interstitial kidney injury and the level of fibrotic proteins. Nr4a1 may contribute to renal fibrosis by activating the p38 MAPK pathway, as treatment with the p38 MAPK inhibitor SB203580 successfully inhibited fibrotic protein expression and p38 MAPK phosphorylation. 184 Furthermore, VDR has been shown to exert a renoprotective effect by inhibiting fibrosis. VDR translocates into the nucleus to form the VDR:RXR heterodimer, which inhibits fibrogenic gene expression in HK-2 cells exposed to high glucose and reduces fibrogenic gene expression in proximal renal tubules. 469 In the aging kidney, the expression of FXR and TGR5 is decreased. However, a dual agonist of FXR and TGR5, INT-767, has been found to reverse age-related kidney disease in mice, demonstrating the therapeutic potential of targeting these receptors in renal aging. 470 In conclusion, nuclear receptors play vital roles in regulating kidney function and protecting against kidney injury and fibrosis. Understanding their mechanisms and interactions could open new avenues for therapeutic strategies to treat kidney diseases, particularly those related to aging and fibrosis.

Application of emerging technologies in NR research

Several challenges remain in targeting NRs therapeutically due to the complexity of NR signaling, tissue specificity, and the need for precise drug design. However, recent advancements in genomics, proteomics, imaging, and computational modeling have enabled more precise exploration of NR function, regulation, and their involvement in various physiological and pathological processes.

Technologies such as ChIP-chip, ChIP-Seq, and GRO-Seq have enabled unbiased, genome-wide profiling of NR binding sites, revealing new insights into NR mechanisms and their regulatory networks in breast cancer. These genomic methods have highlighted the dynamic interactions between NRs and the chromatin landscape. It is increasingly clear that chromatin, in its varying states of condensation, both regulates and is regulated by NR activity, with NR-chromatin interactions playing a major role in cell type-specific transcriptional regulation. 471 Single-cell RNA sequencing (scRNA-seq) has further advanced our understanding of NR function by enabling gene expression analysis at the single-cell level. This technology is invaluable for investigating tissue-specific NR roles and identifying distinct signaling pathways in various cell populations, which is crucial for understanding their contributions to tissue homeostasis, development, and diseases like cancer and metabolic disorders. 472 For instance, single-cell transcriptomics revealed the involvement of a previously uncharacterized retinoic acid receptor family member, SmRAR, in reproductive development in Schistosoma mansoni . 473 CRISPR-Cas9 technology has revolutionized NR research by allowing precise manipulation of genes in vitro and in vivo. This has facilitated studies of NR roles in diseases such as type 2 diabetes, neurodegeneration, and cancer, and provide reversible and tunable control of NR expression, enabling dynamic investigation of NR function. 474 , 475

Recent advances in proteomics, particularly mass spectrometry (MS), have enabled the identification and quantification of NR interactomes, providing insights into the molecular mechanisms regulating NR activity. MS also helps identify post-translational modifications like phosphorylation, acetylation, and SUMOylation, which are crucial for NR activation and signaling. 306 Cryo-EM has emerged as a powerful tool for visualizing the 3D structure of proteins, including NRs, at near-atomic resolution. This technique has provided key insights into the conformational changes NRs undergo upon ligand binding and co-factor recruitment, essential for drug discovery, as many NRs are targeted by small molecules in diseases like cancer, diabetes, and inflammation. 476 For example, cryo-EM has elucidated the assembly of the AR:coactivator complex and its role in coactivator assembly and transcriptional regulation. 70 Additionally, the cryo-EM structure of the NCOA4-FTH1 interface revealed key amino acids crucial for interaction, paving the way for developing ferritinophagy modulators. 477 These technologies, including cryo-EM and omics, have advanced our understanding of NR activation, NR-chromatin interactions, transcriptional regulation, and non-genomic effects, offering new avenues for therapeutic development.

Artificial intelligence (AI) and machine learning (ML) are increasingly applied in NR research to predict receptor-ligand interactions, identify novel signaling pathways, and design drugs targeting specific NR subtypes. These technologies analyze large datasets to uncover hidden patterns within complex biological systems, enhancing our understanding of NRs in health and disease. For example, chemical language models combined with beam search algorithms have been used for automated molecule design, leading to the development of novel inverse agonists for retinoic acid receptor-related orphan receptors (RORs) with low micromolar to nanomolar potency. 478 AI and deep docking methodologies have also facilitated the development of VPC-260724, a novel ER-AF2 binder that inhibits ER activity and exhibits antiproliferative effects in ER-positive breast cancer models. 479 Additionally, AI has been applied to create an adverse outcome pathway (AOP) network for chemical-induced cholestasis, facilitating automated data collection and the identification of key molecular events. 480 Moreover, Bhimsaria and colleagues identified previously hidden binding sites of human NRs via high-throughput SELEX and a novel MinSeq Find algorithm, revealing new biological roles of NRs and their involvement in disease-associated genetic variations while providing a valuable resource for drug repurposing and precision medicine. 481 With AI and ML, high-throughput screening (HTS) has become more efficient, enabling better prediction of drug candidates and optimization of lead compounds for clinical applications.

In vivo imaging techniques like positron emission tomography (PET) and magnetic resonance imaging (MRI) are increasingly used to study nuclear receptor (NR) activity in living organisms. These methods allow real-time tracking of NR signaling and the effects of ligands or drugs on receptor function in tissues. Live-cell imaging with fluorescent biosensors also reveals dynamic interactions between NRs and their co-regulatory proteins at the cellular level. 482 This approach offers a quantitative, in vivo equivalent to classic radioligand binding assays. 483 In vivo imaging helps identify when and where NRs are active during development, aging, and disease, providing insights into how ligands or receptor modulators influence these processes. 484 Other technologies, such as organoids, 3D cell cultures, nanotechnology, and systems biology, have also advanced NR research. Notably, PROTACs (proteolysis-targeting chimeras), which degrade target proteins via the 26S proteasome, offer new possibilities for targeting challenging NRs, including orphan receptors or those without enzymatic activity. In cases of drug resistance due to NR mutations (e.g., in hormone-dependent cancers), PROTACs can bypass resistance by degrading the mutated receptors instead of inhibiting their activity.

Emerging technologies are significantly enhancing the field of nuclear receptor research by providing deeper insights into their structure, function, and regulation. The combination of high-resolution imaging, gene editing tools, and advanced computational techniques has opened new avenues for understanding how NRs control physiological processes and contribute to disease. As these technologies continue to evolve, they hold promise for the development of more precise and effective therapeutic strategies targeting nuclear receptors in a variety of disorders.

Concluding remarks

Nuclear receptors are a crucial class of transcription factors that regulate gene expression in response to various ligands, such as hormones, vitamins and metabolic products. They play pivotal roles in processes such as metabolism, immune responses and development, making them key targets for therapeutic intervention in cardiovascular disease, cancer, metabolic disorders and inflammatory conditions. In recent years, targeted therapies aimed at NRs, such as ERs, ARs and VDRs, have shown significant promise in clinical applications, particularly in oncology and metabolic regulation. Newer nuclear receptors, such as LXR and PXR, are being investigated for their therapeutic potential, revealing novel pathways for drug development.

Despite recent advances, several challenges remain in targeting NRs for therapeutic purposes. One key difficulty is the extensive crosstalk between NRs and their signaling pathways, which can lead to synergistic or antagonistic effects, limiting the effectiveness of targeting a single receptor and causing off-target effects. Additionally, NRs exhibit tissue-specific expression and functional outcomes, making designing drugs that selectively modulate receptor activity in specific tissues or cell types challenging. The specificity of ligand-receptor interactions is another hurdle, as NRs can be activated by various small molecules, and ligand promiscuity or cross-reactivity can lead to unwanted side effects. Moreover, long-term NR modulation may result in side effects or even toxicity, such as liver damage or increased cardiovascular risk. Finally, many NRs are regulated by complex feedback mechanisms, complicating predictions about how receptor activity changes in response to treatment. These dynamic regulatory loops require careful consideration to avoid unintended consequences and therapeutic resistance.

Future research will likely focus on understanding the complex interactions of nuclear receptors in various physiological contexts, developing more selective modulators, and exploring novel strategies for more precise and selective targeting of NRs to minimize off-target effects and enhance therapeutic efficacy. Integration of data from transcriptomics, proteomics, and metabolomics will help model NR signaling networks and predict the effects of targeting a specific NR in the context of broader cellular networks. Structure-based drug design employing leverage X-ray crystallography, cryo-EM, and computational modeling will facilitate the identification or design of small molecules that specifically interact with a target NR’s ligand-binding domain, minimizing cross-reactivity. Cutting-edge technologies such as gene editing CRISPR/Cas9 technology and advanced drug delivery systems achieve tissue- or cell-specific targeting of NRs to minimize off-target effects and enhance therapeutic efficacy. Noninvasive techniques to monitor the activity of NRs via specifically binding imaging agents to activated nuclear receptors or linking reporter genes (e.g., luciferase, GFP) to NR-responsive promoters will allow real-time visualization and quantification of receptor activity in preclinical models. In addition, the fact that NRs are key host sensors of microbial signals offers a promising avenue for gut microbiota-targeted drug discovery by leveraging NR-mediated environmental adaptations. 485 – 487 For example, FXR plays a pivotal role in modulating the gut microbiota and is thereby involved in various biological processes, including the metformin response, 488 bile acid homeostasis, 489 and core metabolic functions. 490 Overall, with the advancement of these technologies, new breakthroughs will be made in the discovery of novel drugs that target NRs.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

These authors contributed equally: Ping Jin, Xirui Duan, Zhao Huang

Acknowledgements

This work was supported by the following research grants: the Department of Science and Technology of Sichuan Province (2023YFS0037), the National Natural Science Foundation of China (32170759, 82303506, 82273126), the Sichuan Administration of Traditional Chinese Medicine (2023MS267), Sichuan Science and Technology Department (2025ZNSFSC1893) the Technological Innovation Research and Development Project from the Chengdu Science and Technology Bureau (2022-YF05-01950-SN) and the Basic Research Program of Yunnan Province (202401CF070184). Figures were created by BioRender (BioRender. com). Data of clinical trials presented in Tables 1 , 2 were obtained from https://clinicaltrials.gov/.

Author contributions

P.J., X.D. and Z.H wrote the manuscript and made the figures, J.Z and H.T revised the Figure, Y.D. and H.G. organized the tables, C.Z. and K.X. conceived, designed, and revised the manuscript. All authors have read and approved the article.

Data availability

Not applicable.

Competing interests

The authors declare no competing interests.

References

1. Cheng X Smith JC Biological membrane organization and cellular signaling Chem. Rev. 2019 119 5849 5880 30747526 10.1021/acs.chemrev.8b00439 Cheng, X. & Smith, J. C. Biological membrane organization and cellular signaling. Chem. Rev. 119 , 5849–5880 (2019). 30747526 10.1021/acs.chemrev.8b00439

2. Ammendolia DA Bement WM Brumell JH Plasma membrane integrity: implications for health and disease BMC Biol. 2021 19 71 33849525 10.1186/s12915-021-00972-y PMC8042475 Ammendolia, D. A., Bement, W. M. & Brumell, J. H. Plasma membrane integrity: implications for health and disease. BMC Biol. 19 , 71 (2021). 33849525 10.1186/s12915-021-00972-y PMC8042475

3. Wang, Z. Regulation of cell cycle progression by growth factor-induced cell signaling. Cells . 10 , 3327 (2021). 10.3390/cells10123327 PMC8699227 34943835

4. Bartlett CS Jeansson M Quaggin SE Vascular growth factors and glomerular disease Annu Rev. Physiol. 2016 78 437 461 26863327 10.1146/annurev-physiol-021115-105412 PMC6450387 Bartlett, C. S., Jeansson, M. & Quaggin, S. E. Vascular growth factors and glomerular disease. Annu Rev. Physiol. 78 , 437–461 (2016). 26863327 10.1146/annurev-physiol-021115-105412 PMC6450387

5. Brown, G. S., Jang, J. & Li, D. Growth factors and their roles in cardiac development and regeneration: a narrative review. Pediatr. Med . 6 , (2022). 10.21037/pm-22-17 PMC13299549 42369579

6. Shindo S Phosphorylation of nuclear receptors: Novelty and therapeutic implications Pharmacol. Ther. 2023 248 108477 37330113 10.1016/j.pharmthera.2023.108477 Shindo, S. et al. Phosphorylation of nuclear receptors: Novelty and therapeutic implications. Pharmacol. Ther. 248 , 108477 (2023). 37330113 10.1016/j.pharmthera.2023.108477

7. Fernandez EJ Allosteric pathways in nuclear receptors - Potential targets for drug design Pharmacol. Ther. 2018 183 152 159 29080700 10.1016/j.pharmthera.2017.10.014 PMC5817003 Fernandez, E. J. Allosteric pathways in nuclear receptors - Potential targets for drug design. Pharmacol. Ther. 183 , 152–159 (2018). 29080700 10.1016/j.pharmthera.2017.10.014 PMC5817003

8. De Bosscher K Nuclear receptor crosstalk - defining the mechanisms for therapeutic innovation Nat. Rev. Endocrinol. 2020 16 363 377 32303708 10.1038/s41574-020-0349-5 De Bosscher, K. et al. Nuclear receptor crosstalk - defining the mechanisms for therapeutic innovation. Nat. Rev. Endocrinol. 16 , 363–377 (2020). 32303708 10.1038/s41574-020-0349-5

9. Pavek P Pregnane X receptor (PXR)-mediated gene repression and cross-talk of PXR with other nuclear receptors via coactivator interactions Front. Pharmacol. 2016 7 456 27932985 10.3389/fphar.2016.00456 PMC5122737 Pavek, P. Pregnane X receptor (PXR)-mediated gene repression and cross-talk of PXR with other nuclear receptors via coactivator interactions. Front. Pharmacol. 7 , 456 (2016). 27932985 10.3389/fphar.2016.00456 PMC5122737

10. Poreba E Durzynska J Nuclear localization and actions of the insulin-like growth factor 1 (IGF-1) system components: Transcriptional regulation and DNA damage response Mutat. Res. Rev. Mutat. Res. 2020 784 108307 32430099 10.1016/j.mrrev.2020.108307 Poreba, E. & Durzynska, J. Nuclear localization and actions of the insulin-like growth factor 1 (IGF-1) system components: Transcriptional regulation and DNA damage response. Mutat. Res. Rev. Mutat. Res. 784 , 108307 (2020). 32430099 10.1016/j.mrrev.2020.108307

11. Porter, B. A., Ortiz, M. A., Bratslavsky, G. & Kotula, L. Structure and Function of the Nuclear Receptor Superfamily and Current Targeted Therapies of Prostate Cancer. Cancers (Basel) . 11 , (2019). 10.3390/cancers11121852 PMC6966469 31771198

12. Butt TR Walfish PG Human nuclear receptor heterodimers: opportunities for detecting targets of transcriptional regulation using yeast Gene Expr. 1996 5 255 268 8723391 PMC6138025 Butt, T. R. & Walfish, P. G. Human nuclear receptor heterodimers: opportunities for detecting targets of transcriptional regulation using yeast. Gene Expr. 5 , 255–268 (1996). 8723391 PMC6138025

13. Penvose A Comprehensive study of nuclear receptor DNA binding provides a revised framework for understanding receptor specificity Nat. Commun. 2019 10 2514 31175293 10.1038/s41467-019-10264-3 PMC6555819 Penvose, A. et al. Comprehensive study of nuclear receptor DNA binding provides a revised framework for understanding receptor specificity. Nat. Commun. 10 , 2514 (2019). 31175293 10.1038/s41467-019-10264-3 PMC6555819

14. Zhang D Heaney AP Nuclear receptors as regulators of pituitary corticotroph pro-opiomelanocortin transcription Cells 2020 9 900 32272677 10.3390/cells9040900 PMC7226830 Zhang, D. & Heaney, A. P. Nuclear receptors as regulators of pituitary corticotroph pro-opiomelanocortin transcription. Cells 9 , 900 (2020). 32272677 10.3390/cells9040900 PMC7226830

15. Wilkenfeld SR Lin C Frigo DE Communication between genomic and non-genomic signaling events coordinate steroid hormone actions Steroids 2018 133 2 7 29155216 10.1016/j.steroids.2017.11.005 PMC5864526 Wilkenfeld, S. R., Lin, C. & Frigo, D. E. Communication between genomic and non-genomic signaling events coordinate steroid hormone actions. Steroids 133 , 2–7 (2018). 29155216 10.1016/j.steroids.2017.11.005 PMC5864526

16. Alegre-Martí A A hotspot for posttranslational modifications on the androgen receptor dimer interface drives pathology and anti-androgen resistance Sci. Adv. 2023 9 eade2175 36921044 10.1126/sciadv.ade2175 PMC10017050 Alegre-Martí, A. et al. A hotspot for posttranslational modifications on the androgen receptor dimer interface drives pathology and anti-androgen resistance. Sci. Adv. 9 , eade2175 (2023). 36921044 10.1126/sciadv.ade2175 PMC10017050

17. Saito, K. & Cui, H. Estrogen receptor alpha splice variants, post-translational modifications, and their physiological functions. Cells . 12 , (2023). 10.3390/cells12060895 PMC10047206 36980236

18. Malbeteau L HoW Protein Methylation Regulates Steroid Receptor Function Endocr. Rev. 2022 43 160 197 33955470 10.1210/endrev/bnab014 PMC8755998 Malbeteau, L. et al. HoW Protein Methylation Regulates Steroid Receptor Function. Endocr. Rev. 43 , 160–197 (2022). 33955470 10.1210/endrev/bnab014 PMC8755998

19. Brunmeir, R. & Xu, F. Functional regulation of ppars through post-translational modifications. Int. J. Mol. Sci . 19 , (2018). 10.3390/ijms19061738 PMC6032173 29895749

20. Fu T FXR regulates intestinal cancer stem cell proliferation Cell 2019 176 1098 1112.e1018 30794774 10.1016/j.cell.2019.01.036 PMC6701863 Fu, T. et al. FXR regulates intestinal cancer stem cell proliferation. Cell 176 , 1098–1112.e1018 (2019). 30794774 10.1016/j.cell.2019.01.036 PMC6701863

21. Ma H The nuclear receptor THRB facilitates differentiation of human PSCs into more mature hepatocytes Cell Stem Cell 2022 29 795 809.e711 35452598 10.1016/j.stem.2022.03.015 PMC9466295 Ma, H. et al. The nuclear receptor THRB facilitates differentiation of human PSCs into more mature hepatocytes. Cell Stem Cell 29 , 795–809.e711 (2022). 35452598 10.1016/j.stem.2022.03.015 PMC9466295

22. Tschuck J Farnesoid X receptor activation by bile acids suppresses lipid peroxidation and ferroptosis Nat. Commun. 2023 14 6908 37903763 10.1038/s41467-023-42702-8 PMC10616197 Tschuck, J. et al. Farnesoid X receptor activation by bile acids suppresses lipid peroxidation and ferroptosis. Nat. Commun. 14 , 6908 (2023). 37903763 10.1038/s41467-023-42702-8 PMC10616197

23. Lambrecht R Liver receptor homolog-1 (NR5A2) orchestrates hepatic inflammation and TNF-induced cell death Cell Rep. 2023 42 113513 38039134 10.1016/j.celrep.2023.113513 Lambrecht, R. et al. Liver receptor homolog-1 (NR5A2) orchestrates hepatic inflammation and TNF-induced cell death. Cell Rep. 42 , 113513 (2023). 38039134 10.1016/j.celrep.2023.113513

24. Meinsohn MC Smith OE Bertolin K Murphy BD The orphan nuclear receptors steroidogenic factor-1 and liver receptor homolog-1: StrUcture, Regulation, And Essential Roles In Mammalian Reproduction Physiol. Rev. 2019 99 1249 1279 30810078 10.1152/physrev.00019.2018 Meinsohn, M. C., Smith, O. E., Bertolin, K. & Murphy, B. D. The orphan nuclear receptors steroidogenic factor-1 and liver receptor homolog-1: StrUcture, Regulation, And Essential Roles In Mammalian Reproduction. Physiol. Rev. 99 , 1249–1279 (2019). 30810078 10.1152/physrev.00019.2018

25. Font-Díaz J Nuclear receptors: Lipid and hormone sensors with essential roles in the control of cancer development Semin. Cancer Biol. 2021 73 58 75 33309851 10.1016/j.semcancer.2020.12.007 Font-Díaz, J. et al. Nuclear receptors: Lipid and hormone sensors with essential roles in the control of cancer development. Semin. Cancer Biol. 73 , 58–75 (2021). 33309851 10.1016/j.semcancer.2020.12.007

26. Zhao L Hu H Gustafsson J Zhou S Nuclear receptors in cancer inflammation and immunity Trends Immunol. 2020 41 172 185 31982345 10.1016/j.it.2019.12.006 Zhao, L., Hu, H., Gustafsson, J. & Zhou, S. Nuclear receptors in cancer inflammation and immunity. Trends Immunol. 41 , 172–185 (2020). 31982345 10.1016/j.it.2019.12.006

27. Yang PB Blocking PPARγ interaction facilitates Nur77 interdiction of fatty acid uptake and suppresses breast cancer progression Proc. Natl. Acad. Sci. USA 2020 117 27412 27422 33087562 10.1073/pnas.2002997117 PMC7959534 Yang, P. B. et al. Blocking PPARγ interaction facilitates Nur77 interdiction of fatty acid uptake and suppresses breast cancer progression. Proc. Natl. Acad. Sci. USA 117 , 27412–27422 (2020). 33087562 10.1073/pnas.2002997117 PMC7959534

28. Wu, Q. et al. Suppressing the intestinal farnesoid X receptor/sphingomyelin phosphodiesterase 3 axis decreases atherosclerosis. J. Clin. Invest . 131 , (2021). 10.1172/JCI142865 PMC8087211 33938457

29. Jiang J Systematic pan-cancer characterization of nuclear receptors identifies potential cancer biomarkers and therapeutic targets Cancer Res 2022 82 46 59 34750098 10.1158/0008-5472.CAN-20-3458 PMC8732309 Jiang, J. et al. Systematic pan-cancer characterization of nuclear receptors identifies potential cancer biomarkers and therapeutic targets. Cancer Res 82 , 46–59 (2022). 34750098 10.1158/0008-5472.CAN-20-3458 PMC8732309

30. Doyon G Bruemmer D Vascular smooth muscle cell dysfunction in diabetes: nuclear receptors channel to relaxation Clin. Sci. (Lond.) 2016 130 1837 1839 27634843 10.1042/CS20160518 Doyon, G. & Bruemmer, D. Vascular smooth muscle cell dysfunction in diabetes: nuclear receptors channel to relaxation. Clin. Sci. (Lond.) 130 , 1837–1839 (2016). 27634843 10.1042/CS20160518

31. Pritchard KI Randomized trial of cyclophosphamide, methotrexate, and fluorouracil chemotherapy added to tamoxifen as adjuvant therapy in postmenopausal women with node-positive estrogen and/or progesterone receptor-positive breast cancer: a report of the National Cancer Institute of Canada Clinical Trials Group. Breast Cancer Site Group J. Clin. Oncol. 1997 15 2302 2311 9196144 10.1200/JCO.1997.15.6.2302 Pritchard, K. I. et al. Randomized trial of cyclophosphamide, methotrexate, and fluorouracil chemotherapy added to tamoxifen as adjuvant therapy in postmenopausal women with node-positive estrogen and/or progesterone receptor-positive breast cancer: a report of the National Cancer Institute of Canada Clinical Trials Group. Breast Cancer Site Group. J. Clin. Oncol. 15 , 2302–2311 (1997). 9196144 10.1200/JCO.1997.15.6.2302

32. Kenda M Sollner Dolenc M Computational study of drugs targeting nuclear receptors Molecules 2020 25 1616 32244747 10.3390/molecules25071616 PMC7180905 Kenda, M. & Sollner Dolenc, M. Computational study of drugs targeting nuclear receptors. Molecules 25 , 1616 (2020). 32244747 10.3390/molecules25071616 PMC7180905

33. van de Wiel SMW Bijsmans ITGW van Mil SWC van de Graaf SFJ Identification of FDA-approved drugs targeting the Farnesoid X Receptor Sci. Rep. 2019 9 2193 30778102 10.1038/s41598-019-38668-7 PMC6379390 van de Wiel, S. M. W., Bijsmans, I. T. G. W., van Mil, S. W. C. & van de Graaf, S. F. J. Identification of FDA-approved drugs targeting the Farnesoid X Receptor. Sci. Rep. 9 , 2193 (2019). 30778102 10.1038/s41598-019-38668-7 PMC6379390

34. Kim H Tamoxifen response at single-cell resolution in estrogen receptor-positive primary human breast tumors Clin. Cancer Res. 2023 29 4894 4907 37747807 10.1158/1078-0432.CCR-23-1248 PMC10690085 Kim, H. et al. Tamoxifen response at single-cell resolution in estrogen receptor-positive primary human breast tumors. Clin. Cancer Res. 29 , 4894–4907 (2023). 37747807 10.1158/1078-0432.CCR-23-1248 PMC10690085

35. Zhang N Identifying actionable druggable targets for breast cancer: Mendelian randomization and population-based analyses EBioMedicine 2023 98 104859 38251461 10.1016/j.ebiom.2023.104859 PMC10628347 Zhang, N. et al. Identifying actionable druggable targets for breast cancer: Mendelian randomization and population-based analyses. EBioMedicine 98 , 104859 (2023). 38251461 10.1016/j.ebiom.2023.104859 PMC10628347

36. Freedland SJ Improved outcomes with enzalutamide in biochemically recurrent prostate cancer N. Engl. J. Med. 2023 389 1453 1465 37851874 10.1056/NEJMoa2303974 Freedland, S. J. et al. Improved outcomes with enzalutamide in biochemically recurrent prostate cancer. N. Engl. J. Med. 389 , 1453–1465 (2023). 37851874 10.1056/NEJMoa2303974

37. Armstrong AJ Improved survival with enzalutamide in patients with metastatic hormone-sensitive prostate cancer J. Clin. Oncol. 2022 40 1616 1622 35420921 10.1200/JCO.22.00193 PMC9113211 Armstrong, A. J. et al. Improved survival with enzalutamide in patients with metastatic hormone-sensitive prostate cancer. J. Clin. Oncol. 40 , 1616–1622 (2022). 35420921 10.1200/JCO.22.00193 PMC9113211

38. Lazar MA Reversing the curse on PPARγ J. Clin. Invest. 2018 128 2202 2204 29757190 10.1172/JCI121392 PMC5983334 Lazar, M. A. Reversing the curse on PPARγ. J. Clin. Invest. 128 , 2202–2204 (2018). 29757190 10.1172/JCI121392 PMC5983334

39. Dormandy JA Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial Lancet 2005 366 1279 1289 16214598 10.1016/S0140-6736(05)67528-9 Dormandy, J. A. et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 366 , 1279–1289 (2005). 16214598 10.1016/S0140-6736(05)67528-9

40. Huss JM Kelly DP Nuclear receptor signaling and cardiac energetics Circ. Res. 2004 95 568 578 15375023 10.1161/01.RES.0000141774.29937.e3 Huss, J. M. & Kelly, D. P. Nuclear receptor signaling and cardiac energetics. Circ. Res. 95 , 568–578 (2004). 15375023 10.1161/01.RES.0000141774.29937.e3

41. Vega RB Kelly DP Cardiac nuclear receptors: architects of mitochondrial structure and function J. Clin. Invest. 2017 127 1155 1164 28192373 10.1172/JCI88888 PMC5373869 Vega, R. B. & Kelly, D. P. Cardiac nuclear receptors: architects of mitochondrial structure and function. J. Clin. Invest. 127 , 1155–1164 (2017). 28192373 10.1172/JCI88888 PMC5373869

42. Vance ML Growth-hormone-releasing hormone Clin. Chem. 1990 36 415 420 2107038 Vance, M. L. Growth-hormone-releasing hormone. Clin. Chem. 36 , 415–420 (1990). 2107038

43. Xu HE Family reunion of nuclear hormone receptors: Structures, diseases, and drug discovery Acta Pharm. Sin. 2015 36 1 2 10.1038/aps.2014.140 PMC4571322 25557215 Xu, H. E. Family reunion of nuclear hormone receptors: Structures, diseases, and drug discovery. Acta Pharm. Sin. 36 , 1–2 (2015). 10.1038/aps.2014.140 PMC4571322 25557215

44. Henderson J Ernest Starling and ‘Hormones’: An historical commentary J. Endocrinol. 2005 184 5 10 15642778 10.1677/joe.1.06000 Henderson, J. Ernest Starling and ‘Hormones’: An historical commentary. J. Endocrinol. 184 , 5–10 (2005). 15642778 10.1677/joe.1.06000

45. Bussmann, B. et al. Bayliss Starling Prize Lecture 2023: Neuropeptide-Y being ‘unsympathetic’ to the broken hearted. J. Physiol. 603 , 1841–1864 (2024). 10.1113/JP285370 PMC11955873 38847435

46. Raju TN The Nobel chronicles. 1950: Edward Calvin Kendall (1886-1972); Philip Showalter Hench (1896-1965); and Tadeus Reichstein (1897-1996) Lancet 1999 353 1370 10218568 10.1016/s0140-6736(05)74374-9 Raju, T. N. The Nobel chronicles. 1950: Edward Calvin Kendall (1886-1972); Philip Showalter Hench (1896-1965); and Tadeus Reichstein (1897-1996). Lancet 353 , 1370 (1999). 10218568 10.1016/s0140-6736(05)74374-9

47. Shampo MA Kyle RA Steensma DP Adolf Butenandt-Nobel Prize for chemistry Mayo Clin. Proc. 2012 87 e27 22469359 10.1016/j.mayocp.2011.12.019 PMC3498200 Shampo, M. A., Kyle, R. A. & Steensma, D. P. Adolf Butenandt-Nobel Prize for chemistry. Mayo Clin. Proc. 87 , e27 (2012). 22469359 10.1016/j.mayocp.2011.12.019 PMC3498200

48. Simoni RD Hill RL Vaughan M The discovery of estrone, estriol, and estradiol and the biochemical study of reproduction. The work of Edward Adelbert Doisy J. Biol. Chem. 2002 277 e1 e2 Simoni, R. D., Hill, R. L. & Vaughan, M. The discovery of estrone, estriol, and estradiol and the biochemical study of reproduction. The work of Edward Adelbert Doisy. J. Biol. Chem. 277 , e1–e2 (2002).12061339

49. O’Malley BW Khan S Elwood V Jensen (1920-2012): father of the nuclear receptors Proc. Natl. Acad. Sci. USA 2013 110 3707 3708 23471960 10.1073/pnas.1301566110 PMC3593867 O’Malley, B. W., Khan, S. & Elwood, V. Jensen (1920-2012): father of the nuclear receptors. Proc. Natl. Acad. Sci. USA 110 , 3707–3708 (2013). 23471960 10.1073/pnas.1301566110 PMC3593867

50. Hollenberg SM Giguere V Segui P Evans RM Colocalization of DNA-binding and transcriptional activation functions in the human glucocorticoid receptor Cell 1987 49 39 46 3829127 10.1016/0092-8674(87)90753-7 Hollenberg, S. M., Giguere, V., Segui, P. & Evans, R. M. Colocalization of DNA-binding and transcriptional activation functions in the human glucocorticoid receptor. Cell 49 , 39–46 (1987). 3829127 10.1016/0092-8674(87)90753-7

51. Weinberger C Identification of human glucocorticoid receptor complementary DNA clones by epitope selection Sci 1985 228 740 742 10.1126/science.2581314 2581314 Weinberger, C. et al. Identification of human glucocorticoid receptor complementary DNA clones by epitope selection. Sci 228 , 740–742 (1985). 10.1126/science.2581314 2581314

52. Frigo DE Bondesson M Williams C Nuclear receptors: From molecular mechanisms to therapeutics Essays Biochem 2021 65 847 856 34825698 10.1042/EBC20210020 PMC8628184 Frigo, D. E., Bondesson, M. & Williams, C. Nuclear receptors: From molecular mechanisms to therapeutics. Essays Biochem 65 , 847–856 (2021). 34825698 10.1042/EBC20210020 PMC8628184

53. Obiorah IE Fan P Jordan VC Breast cancer cell apoptosis with phytoestrogens is dependent on an estrogen-deprived state Cancer Prev. Res. 2014 7 939 949 10.1158/1940-6207.CAPR-14-0061 24894196 Obiorah, I. E., Fan, P. & Jordan, V. C. Breast cancer cell apoptosis with phytoestrogens is dependent on an estrogen-deprived state. Cancer Prev. Res. 7 , 939–949 (2014). 10.1158/1940-6207.CAPR-14-0061 24894196

54. Mohd Idris, R. A. et al. The effects of tamoxifen on tolerogenic cells in cancer. Biology (Basel) . 11 , (2022). 10.3390/biology11081225 PMC9405160 36009853

55. Shiota, M., Fujimoto, N., Kashiwagi, E. & Eto, M. The role of nuclear receptors in prostate cancer. Cells . 8 , (2019). 10.3390/cells8060602 PMC6627805 31212954

56. Ramesh S State-of-the-art therapeutic strategies for targeting cancer stem cells in prostate cancer Front. Oncol. 2023 13 1059441 36969009 10.3389/fonc.2023.1059441 PMC10035756 Ramesh, S. et al. State-of-the-art therapeutic strategies for targeting cancer stem cells in prostate cancer. Front. Oncol. 13 , 1059441 (2023). 36969009 10.3389/fonc.2023.1059441 PMC10035756

57. Hsu E-C Trop2 is a driver of metastatic prostate cancer with neuroendocrine phenotype via PARP1 Proc. Natl. Acad. Sci. USA 2020 117 2032 2042 31932422 10.1073/pnas.1905384117 PMC6994991 Hsu, E.-C. et al. Trop2 is a driver of metastatic prostate cancer with neuroendocrine phenotype via PARP1. Proc. Natl. Acad. Sci. USA 117 , 2032–2042 (2020). 31932422 10.1073/pnas.1905384117 PMC6994991

58. Ghosh A Tripathy A Ghosh D Impact of endocrine disrupting chemicals (EDCs) on reproductive health of human Proc. Zool. Soc. 2022 75 16 30 Ghosh, A., Tripathy, A. & Ghosh, D. Impact of endocrine disrupting chemicals (EDCs) on reproductive health of human. Proc. Zool. Soc. 75 , 16–30 (2022).

59. Mazaira, G. I. et al. The nuclear receptor field: A historical overview and future challenges. Nucl. Receptor Res . 5 , (2018). 10.11131/2018/101320 PMC6108593 30148160

60. Ellmann S Estrogen and progesterone receptors: From molecular structures to clinical targets Cell. Mol. Life Sci. 2009 66 2405 2426 19333551 10.1007/s00018-009-0017-3 PMC11115849 Ellmann, S. et al. Estrogen and progesterone receptors: From molecular structures to clinical targets. Cell. Mol. Life Sci. 66 , 2405–2426 (2009). 19333551 10.1007/s00018-009-0017-3 PMC11115849

61. Paakinaho V Palvimo JJ Genome-wide crosstalk between steroid receptors in breast and prostate cancers Endocr. Relat. Cancer 2021 28 R231 R250 34137734 10.1530/ERC-21-0038 PMC8345902 Paakinaho, V. & Palvimo, J. J. Genome-wide crosstalk between steroid receptors in breast and prostate cancers. Endocr. Relat. Cancer 28 , R231–R250 (2021). 34137734 10.1530/ERC-21-0038 PMC8345902

62. Bridgham JT Carroll SM Thornton JW Evolution of hormone-receptor complexity by molecular exploitation Sci 2006 312 97 101 10.1126/science.1123348 16601189 Bridgham, J. T., Carroll, S. M. & Thornton, J. W. Evolution of hormone-receptor complexity by molecular exploitation. Sci 312 , 97–101 (2006). 10.1681/01.asn.0000926836.46869.e5 37000978

63. Dube N Khan SH Sasse R Okafor CD Identification of an evolutionarily conserved allosteric network in steroid receptors J. Chem. Inf. Model. 2023 63 571 582 36594606 10.1021/acs.jcim.2c01096 PMC9875803 Dube, N., Khan, S. H., Sasse, R. & Okafor, C. D. Identification of an evolutionarily conserved allosteric network in steroid receptors. J. Chem. Inf. Model. 63 , 571–582 (2023). 36594606 10.1021/acs.jcim.2c01096 PMC9875803

64. Hantusch B Targeting androgen, thyroid hormone, and vitamin A and D receptors to treat prostate cancer Int. J. Mol. Sci. 2024 25 9245 39273194 10.3390/ijms25179245 PMC11394715 Hantusch, B. et al. Targeting androgen, thyroid hormone, and vitamin A and D receptors to treat prostate cancer. Int. J. Mol. Sci. 25 , 9245 (2024). 39273194 10.3390/ijms25179245 PMC11394715

65. Sever R Glass CK Signaling by nuclear receptors Cold Spring Harb. Perspect. Biol. 2013 5 a016709 23457262 10.1101/cshperspect.a016709 PMC3578364 Sever, R. & Glass, C. K. Signaling by nuclear receptors. Cold Spring Harb. Perspect. Biol. 5 , a016709 (2013). 23457262 10.1101/cshperspect.a016709 PMC3578364

66. Xu, P. Nuclear receptors in health and diseases. Int. J. Mol. Sci . 24 , (2023). 10.3390/ijms24119153 PMC10252477 37298107

67. Gissendanner CR Expression and function of conserved nuclear receptor genes in Caenorhabditis elegans Dev. Biol. 2004 266 399 416 14738886 10.1016/j.ydbio.2003.10.014 Gissendanner, C. R. et al. Expression and function of conserved nuclear receptor genes in Caenorhabditis elegans. Dev. Biol. 266 , 399–416 (2004). 14738886 10.1016/j.ydbio.2003.10.014

68. D’Arrigo, G. et al. Exploring ligand binding domain dynamics in the NRs superfamily. Int. J. Mol. Sci . 23 , (2022). 10.3390/ijms23158732 PMC9369052 35955864

69. Lavery DN McEwan IJ Structure and function of steroid receptor AF1 transactivation domains: Induction of active conformations Biochem J. 2005 391 449 464 16238547 10.1042/BJ20050872 PMC1276946 Lavery, D. N. & McEwan, I. J. Structure and function of steroid receptor AF1 transactivation domains: Induction of active conformations. Biochem J. 391 , 449–464 (2005). 16238547 10.1042/BJ20050872 PMC1276946

70. Yu X Structural insights of transcriptionally active, full-length androgen receptor coactivator complexes Mol. Cell 2020 79 812 823.e814 32668201 10.1016/j.molcel.2020.06.031 PMC7483370 Yu, X. et al. Structural insights of transcriptionally active, full-length androgen receptor coactivator complexes. Mol. Cell 79 , 812–823.e814 (2020). 32668201 10.1016/j.molcel.2020.06.031 PMC7483370

71. Fernandez EJ Gahlot V Rodriguez C Amburn J DNA-induced unfolding of the thyroid hormone receptor α A/B domain through allostery FEBS Open Bio 2017 7 854 864 28593140 10.1002/2211-5463.12229 PMC5458466 Fernandez, E. J., Gahlot, V., Rodriguez, C. & Amburn, J. DNA-induced unfolding of the thyroid hormone receptor α A/B domain through allostery. FEBS Open Bio 7 , 854–864 (2017). 28593140 10.1002/2211-5463.12229 PMC5458466

72. Xie G Centrosomal localization of RXRα promotes PLK1 activation and mitotic progression and constitutes a tumor vulnerability Dev. Cell. 2020 55 707 722.e709 33321102 10.1016/j.devcel.2020.11.012 Xie, G. et al. Centrosomal localization of RXRα promotes PLK1 activation and mitotic progression and constitutes a tumor vulnerability. Dev. Cell. 55 , 707–722.e709 (2020). 33321102 10.1016/j.devcel.2020.11.012

73. Ma B De novo design of an androgen receptor DNA binding domain-targeted peptide PROTAC for prostate cancer therapy Adv. Sci. (Weinh.) 2022 9 e2201859 35971165 10.1002/advs.202201859 PMC9534960 Ma, B. et al. De novo design of an androgen receptor DNA binding domain-targeted peptide PROTAC for prostate cancer therapy. Adv. Sci. (Weinh.) 9 , e2201859 (2022). 35971165 10.1002/advs.202201859 PMC9534960

74. Choi WJ Haratipour Z Blind RD Full-length nuclear receptor allosteric regulation J. Lipid Res 2023 64 100406 37356665 10.1016/j.jlr.2023.100406 PMC10388211 Choi, W. J., Haratipour, Z. & Blind, R. D. Full-length nuclear receptor allosteric regulation. J. Lipid Res . 64 , 100406 (2023). 37356665 10.1016/j.jlr.2023.100406 PMC10388211

75. Liu Y Structures of human TR4LBD-JAZF1 and TR4DBD-DNA complexes reveal the molecular basis of transcriptional regulation Nucleic Acids Res. 2023 51 1443 1457 36651297 10.1093/nar/gkac1259 PMC9943680 Liu, Y. et al. Structures of human TR4LBD-JAZF1 and TR4DBD-DNA complexes reveal the molecular basis of transcriptional regulation. Nucleic Acids Res. 51 , 1443–1457 (2023). 36651297 10.1093/nar/gkac1259 PMC9943680

76. Wasmuth EV Allosteric interactions prime androgen receptor dimerization and activation Mol. Cell 2022 82 2021 2031.e2025 35447082 10.1016/j.molcel.2022.03.035 PMC9177810 Wasmuth, E. V. et al. Allosteric interactions prime androgen receptor dimerization and activation. Mol. Cell 82 , 2021–2031.e2025 (2022). 35447082 10.1016/j.molcel.2022.03.035 PMC9177810

77. Kolonko M The intrinsically disordered region of GCE protein adopts a more fixed structure by interacting with the LBD of the nuclear receptor FTZ-F1 Cell Commun. Signal 2020 18 180 33153474 10.1186/s12964-020-00662-2 PMC7643343 Kolonko, M. et al. The intrinsically disordered region of GCE protein adopts a more fixed structure by interacting with the LBD of the nuclear receptor FTZ-F1. Cell Commun. Signal 18 , 180 (2020). 33153474 10.1186/s12964-020-00662-2 PMC7643343

78. Fang N Identification of a novel melatonin-binding nuclear receptor: Vitamin D receptor J. Pineal Res 2020 68 e12618 31631405 10.1111/jpi.12618 Fang, N. et al. Identification of a novel melatonin-binding nuclear receptor: Vitamin D receptor. J. Pineal Res 68 , e12618 (2020). 31631405 10.1111/jpi.12618

79. Erratum: Recognition of fold- and function-specific sites in the ligand-binding domain of the thyroid hormone receptor-like family. Front. Endocrinol. (Lausanne) . 14 , 1175369, (2023). 10.3389/fendo.2023.1175369 PMC10036899 36967784

80. Webb P Estrogen receptor activation function 1 works by binding p160 coactivator proteins Mol. Endocrinol. 1998 12 1605 1618 9773983 10.1210/mend.12.10.0185 Webb, P. et al. Estrogen receptor activation function 1 works by binding p160 coactivator proteins. Mol. Endocrinol. 12 , 1605–1618 (1998). 9773983 10.1210/mend.12.10.0185

81. Nakadai T Two target gene activation pathways for orphan ERR nuclear receptors Cell Res 2023 33 165 183 36646760 10.1038/s41422-022-00774-z PMC9892517 Nakadai, T. et al. Two target gene activation pathways for orphan ERR nuclear receptors. Cell Res . 33 , 165–183 (2023). 36646760 10.1038/s41422-022-00774-z PMC9892517

82. Useini A Engelberger F Künze G Sträter N Structural basis of the activation of PPARγ by the plasticizer metabolites MEHP and MINCH Environ. Int. 2023 173 107822 36841188 10.1016/j.envint.2023.107822 Useini, A., Engelberger, F., Künze, G. & Sträter, N. Structural basis of the activation of PPARγ by the plasticizer metabolites MEHP and MINCH. Environ. Int. 173 , 107822 (2023). 36841188 10.1016/j.envint.2023.107822

83. Louw A GR dimerization and the impact of GR dimerization on GR protein stability and half-life Front. Immunol. 2019 10 1693 31379877 10.3389/fimmu.2019.01693 PMC6653659 Louw, A. GR dimerization and the impact of GR dimerization on GR protein stability and half-life. Front. Immunol. 10 , 1693 (2019). 31379877 10.3389/fimmu.2019.01693 PMC6653659

84. Huang W Multidomain architecture of estrogen receptor reveals interfacial cross-talk between its DNA-binding and ligand-binding domains Nat. Commun. 2018 9 3520 30166540 10.1038/s41467-018-06034-2 PMC6117352 Huang, W. et al. Multidomain architecture of estrogen receptor reveals interfacial cross-talk between its DNA-binding and ligand-binding domains. Nat. Commun. 9 , 3520 (2018). 30166540 10.1038/s41467-018-06034-2 PMC6117352

85. da Silva MA Case report: Two novel PPARG pathogenic variants associated with type 3 familial partial lipodystrophy in Brazil Diabetol. Metab. Syndr. 2024 16 145 38951919 10.1186/s13098-024-01387-9 PMC11218129 da Silva, M. A. et al. Case report: Two novel PPARG pathogenic variants associated with type 3 familial partial lipodystrophy in Brazil. Diabetol. Metab. Syndr. 16 , 145 (2024). 38951919 10.1186/s13098-024-01387-9 PMC11218129

86. Lu J Types of nuclear localization signals and mechanisms of protein import into the nucleus Cell Commun. Signal. 2021 19 60 34022911 10.1186/s12964-021-00741-y PMC8140498 Lu, J. et al. Types of nuclear localization signals and mechanisms of protein import into the nucleus. Cell Commun. Signal. 19 , 60 (2021). 34022911 10.1186/s12964-021-00741-y PMC8140498

87. Nagandla H Thomas C Estrogen signals through ERβ in breast cancer; what we have learned since the discovery of the receptor Receptors 2024 3 182 200 39175529 10.3390/receptors3020010 PMC11340209 Nagandla, H. & Thomas, C. Estrogen signals through ERβ in breast cancer; what we have learned since the discovery of the receptor. Receptors 3 , 182–200 (2024). 39175529 10.3390/receptors3020010 PMC11340209

88. Huang W Evolution of a novel nuclear receptor subfamily with emphasis on the member from the Pacific oyster Crassostrea gigas Gene 2015 567 164 172 25956376 10.1016/j.gene.2015.04.082 Huang, W. et al. Evolution of a novel nuclear receptor subfamily with emphasis on the member from the Pacific oyster Crassostrea gigas. Gene 567 , 164–172 (2015). 25956376 10.1016/j.gene.2015.04.082

89. Więch, A., Tarczewska, A., Ożyhar, A. & Orłowski, M. Metal ions induce liquid condensate formation by the f domain of aedes aegypti ecdysteroid receptor. New perspectives of nuclear receptor studies. Cells . 10 , (2021). 10.3390/cells10030571 PMC7999165 33807814

90. Jakób M Novel DNA-binding element within the C-terminal extension of the nuclear receptor DNA-binding domain Nucleic Acids Res 2007 35 2705 2718 17426125 10.1093/nar/gkm162 PMC1885670 Jakób, M. et al. Novel DNA-binding element within the C-terminal extension of the nuclear receptor DNA-binding domain. Nucleic Acids Res . 35 , 2705–2718 (2007). 17426125 10.1093/nar/gkm162 PMC1885670

91. Arao Y Korach KennethS The physiological role of estrogen receptor functional domains Essays Biochem 2021 65 867 875 34028522 10.1042/EBC20200167 PMC8611119 Arao, Y. & Korach, K. ennethS. The physiological role of estrogen receptor functional domains. Essays Biochem 65 , 867–875 (2021). 34028522 10.1042/EBC20200167 PMC8611119

92. Baker ME Origin and diversification of steroids: co-evolution of enzymes and nuclear receptors Mol. Cell Endocrinol. 2011 334 14 20 20654689 10.1016/j.mce.2010.07.013 Baker, M. E. Origin and diversification of steroids: co-evolution of enzymes and nuclear receptors. Mol. Cell Endocrinol. 334 , 14–20 (2011). 20654689 10.1016/j.mce.2010.07.013

93. Magner DB Antebi A Caenorhabditis elegans nuclear receptors: insights into life traits Trends Endocrinol. Metab. 2008 19 153 160 18406164 10.1016/j.tem.2008.02.005 PMC2744080 Magner, D. B. & Antebi, A. Caenorhabditis elegans nuclear receptors: insights into life traits. Trends Endocrinol. Metab. 19 , 153–160 (2008). 18406164 10.1016/j.tem.2008.02.005 PMC2744080

94. Schulman IG Heyman RA The flip side: Identifying small molecule regulators of nuclear receptors Chem. Biol. 2004 11 639 646 15157874 10.1016/j.chembiol.2003.12.021 Schulman, I. G. & Heyman, R. A. The flip side: Identifying small molecule regulators of nuclear receptors. Chem. Biol. 11 , 639–646 (2004). 15157874 10.1016/j.chembiol.2003.12.021

95. Jobe A Vijayan R Orphan G protein-coupled receptors: the ongoing search for a home Front. Pharmacol. 2024 15 1349097 38495099 10.3389/fphar.2024.1349097 PMC10941346 Jobe, A. & Vijayan, R. Orphan G protein-coupled receptors: the ongoing search for a home. Front. Pharmacol. 15 , 1349097 (2024). 38495099 10.3389/fphar.2024.1349097 PMC10941346

96. Siepe DH Identification of orphan ligand-receptor relationships using a cell-based CRISPRa enrichment screening platform eLife 2022 11 e81398 36178190 10.7554/eLife.81398 PMC9578707 Siepe, D. H. et al. Identification of orphan ligand-receptor relationships using a cell-based CRISPRa enrichment screening platform. eLife 11 , e81398 (2022). 36178190 10.7554/eLife.81398 PMC9578707

97. Thornton JW Evolution of vertebrate steroid receptors from an ancestral estrogen receptor by ligand exploitation and serial genome expansions Proc. Natl. Acad. Sci. USA 2001 98 5671 5676 11331759 10.1073/pnas.091553298 PMC33271 Thornton, J. W. Evolution of vertebrate steroid receptors from an ancestral estrogen receptor by ligand exploitation and serial genome expansions. Proc. Natl. Acad. Sci. USA 98 , 5671–5676 (2001). 11331759 10.1073/pnas.091553298 PMC33271

98. Escriva H Delaunay F Laudet V Ligand binding and nuclear receptor evolution Bioessays 2000 22 717 727 10918302 10.1002/1521-1878(200008)22:8<717::AID-BIES5>3.0.CO;2-I Escriva, H., Delaunay, F. & Laudet, V. Ligand binding and nuclear receptor evolution. Bioessays 22 , 717–727 (2000). 10918302 10.1002/1521-1878(200008)22:8<717::AID-BIES5>3.0.CO;2-I

99. Laudet V Evolution of the nuclear receptor gene superfamily EMBO J. 1992 11 1003 1013 1312460 10.1002/j.1460-2075.1992.tb05139.x PMC556541 Laudet, V. et al. Evolution of the nuclear receptor gene superfamily. EMBO J. 11 , 1003–1013 (1992). 1312460 10.1002/j.1460-2075.1992.tb05139.x PMC556541

100. Laudet V Evolution of the nuclear receptor superfamily: early diversification from an ancestral orphan receptor J. Mol. Endocrinol. 1997 19 207 226 9460643 10.1677/jme.0.0190207 Laudet, V. Evolution of the nuclear receptor superfamily: early diversification from an ancestral orphan receptor. J. Mol. Endocrinol. 19 , 207–226 (1997). 9460643 10.1677/jme.0.0190207

101. Markov GV Laudet V Origin and evolution of the ligand-binding ability of nuclear receptors Mol. Cell Endocrinol. 2011 334 21 30 21055443 10.1016/j.mce.2010.10.017 Markov, G. V. & Laudet, V. Origin and evolution of the ligand-binding ability of nuclear receptors. Mol. Cell Endocrinol. 334 , 21–30 (2011). 21055443 10.1016/j.mce.2010.10.017

102. Beinsteiner B A novel nuclear receptor subfamily enlightens the origin of heterodimerization BMC Biol. 2022 20 217 36199108 10.1186/s12915-022-01413-0 PMC9535869 Beinsteiner, B. et al. A novel nuclear receptor subfamily enlightens the origin of heterodimerization. BMC Biol. 20 , 217 (2022). 36199108 10.1186/s12915-022-01413-0 PMC9535869

103. Bwayi MN Molecular basis of crosstalk in nuclear receptors: Heterodimerization between PXR and CAR and the implication in gene regulation Nucleic Acids Res. 2022 50 3254 3275 35212371 10.1093/nar/gkac133 PMC8989523 Bwayi, M. N. et al. Molecular basis of crosstalk in nuclear receptors: Heterodimerization between PXR and CAR and the implication in gene regulation. Nucleic Acids Res. 50 , 3254–3275 (2022). 35212371 10.1093/nar/gkac133 PMC8989523

104. De Bosscher K Nuclear receptor crosstalk — defining the mechanisms for therapeutic innovation Nat. Rev. Endocrinol. 2020 16 363 377 32303708 10.1038/s41574-020-0349-5 De Bosscher, K. et al. Nuclear receptor crosstalk — defining the mechanisms for therapeutic innovation. Nat. Rev. Endocrinol. 16 , 363–377 (2020). 32303708 10.1038/s41574-020-0349-5

105. Ogawa S Molecular determinants of crosstalk between nuclear receptors and toll-like receptors Cell 2005 122 707 721 16143103 10.1016/j.cell.2005.06.029 PMC1430687 Ogawa, S. et al. Molecular determinants of crosstalk between nuclear receptors and toll-like receptors. Cell 122 , 707–721 (2005). 16143103 10.1016/j.cell.2005.06.029 PMC1430687

106. Huggins RJ Greene GL ERα/PR crosstalk is altered in the context of the ERα Y537S mutation and contributes to endocrine therapy-resistant tumor proliferation npj Breast Cancer 2023 9 96 38036546 10.1038/s41523-023-00601-7 PMC10689488 Huggins, R. J. & Greene, G. L. ERα/PR crosstalk is altered in the context of the ERα Y537S mutation and contributes to endocrine therapy-resistant tumor proliferation. npj Breast Cancer 9 , 96 (2023). 38036546 10.1038/s41523-023-00601-7 PMC10689488

107. Katzenellenbogen B Katzenellenbogen BS Mechanisms of action and cross-talk between estrogen receptor and progesterone receptor pathways. J Soc Gynecol Investig 71(Suppl): S33-S37 J. Soc. Gynecol. Investig. 2000 7 S33 S37 10732327 10.1016/s1071-5576(99)00058-1 Katzenellenbogen, B. & Katzenellenbogen, B. S. Mechanisms of action and cross-talk between estrogen receptor and progesterone receptor pathways. J Soc Gynecol Investig 71(Suppl): S33-S37. J. Soc. Gynecol. Investig. 7 , S33–S37 (2000). 10732327 10.1016/s1071-5576(99)00058-1

108. Ratman D Chromatin recruitment of activated AMPK drives fasting response genes co-controlled by GR and PPARα Nucleic Acids Res. 2016 44 10539 10553 27576532 10.1093/nar/gkw742 PMC5159533 Ratman, D. et al. Chromatin recruitment of activated AMPK drives fasting response genes co-controlled by GR and PPARα. Nucleic Acids Res. 44 , 10539–10553 (2016). 27576532 10.1093/nar/gkw742 PMC5159533

109. Bougarne N Mechanisms underlying the functional cooperation between PPARα and GRα to attenuate inflammatory responses Front. Immunol. 2019 10 1769 31447832 10.3389/fimmu.2019.01769 PMC6695567 Bougarne, N. et al. Mechanisms underlying the functional cooperation between PPARα and GRα to attenuate inflammatory responses. Front. Immunol. 10 , 1769 (2019). 31447832 10.3389/fimmu.2019.01769 PMC6695567

110. Dana N Vaseghi G Haghjooy Javanmard S Activation of PPARγ inhibits TLR4 signal transduction pathway in melanoma cancer in vitro Adv. Pharm. Bull. 2020 10 458 463 32665906 10.34172/apb.2020.056 PMC7335991 Dana, N., Vaseghi, G. & Haghjooy Javanmard, S. Activation of PPARγ inhibits TLR4 signal transduction pathway in melanoma cancer in vitro. Adv. Pharm. Bull. 10 , 458–463 (2020). 32665906 10.34172/apb.2020.056 PMC7335991

111. Toobian, D., Ghosh, P. & Katkar, G. D. Parsing the role of PPARs in macrophage processes. Front. Immunol . 12 , (2021). 10.3389/fimmu.2021.783780 PMC8727354 35003101

112. Cantile, M. et al. Endocrine nuclear receptors and long non‑coding RNAs reciprocal regulation in cancer (Review). Int. J. Oncol . 64 , (2024). 10.3892/ijo.2023.5595 PMC10705039 38038050

113. Freire PR Conneely OM NR4A1 and NR4A3 restrict HSC proliferation via reciprocal regulation of C/EBPα and inflammatory signaling Blood 2018 131 1081 1093 29343483 10.1182/blood-2017-07-795757 PMC5863701 Freire, P. R. & Conneely, O. M. NR4A1 and NR4A3 restrict HSC proliferation via reciprocal regulation of C/EBPα and inflammatory signaling. Blood 131 , 1081–1093 (2018). 29343483 10.1182/blood-2017-07-795757 PMC5863701

114. Gao, H., Li, Y. & Chen, X. Interactions between nuclear receptors glucocorticoid receptor α and peroxisome proliferator–activated receptor α form a negative feedback loop. Rev. Endocr. Metab. Disord . 23 , (2022). 10.1007/s11154-022-09725-w 35476174

115. Bougarne N PPARα blocks glucocorticoid receptor α-mediated transactivation but cooperates with the activated glucocorticoid receptor α for transrepression on NF-κB Proc. Natl. Acad. Sci. USA 2009 106 7397 7402 19376972 10.1073/pnas.0806742106 PMC2678648 Bougarne, N. et al. PPARα blocks glucocorticoid receptor α-mediated transactivation but cooperates with the activated glucocorticoid receptor α for transrepression on NF-κB. Proc. Natl. Acad. Sci. USA 106 , 7397–7402 (2009). 19376972 10.1073/pnas.0806742106 PMC2678648

116. Chen X Peroxisome proliferator-activated receptor alpha agonist-induced down-regulation of hepatic glucocorticoid receptor expression in SD rats Biochem. Biophys. Res Commun. 2008 368 865 870 18267115 10.1016/j.bbrc.2008.01.152 Chen, X. et al. Peroxisome proliferator-activated receptor alpha agonist-induced down-regulation of hepatic glucocorticoid receptor expression in SD rats. Biochem. Biophys. Res Commun. 368 , 865–870 (2008). 18267115 10.1016/j.bbrc.2008.01.152

117. Cadoudal T Proposed involvement of adipocyte glyceroneogenesis and phosphoenolpyruvate carboxykinase in the metabolic syndrome Biochimie 2005 87 27 32 15733733 10.1016/j.biochi.2004.12.005 Cadoudal, T. et al. Proposed involvement of adipocyte glyceroneogenesis and phosphoenolpyruvate carboxykinase in the metabolic syndrome. Biochimie 87 , 27–32 (2005). 15733733 10.1016/j.biochi.2004.12.005

118. Antwi MB Unlocking therapeutic potential: Exploring cross-talk among emerging nuclear receptors to combat metabolic dysfunction in steatotic liver disease npj Metab. Health Dis. 2024 2 13 40603501 10.1038/s44324-024-00013-6 PMC12118758 Antwi, M. B. et al. Unlocking therapeutic potential: Exploring cross-talk among emerging nuclear receptors to combat metabolic dysfunction in steatotic liver disease. npj Metab. Health Dis. 2 , 13 (2024). 40603501 10.1038/s44324-024-00013-6 PMC12118758

119. Wang J Forsythiaside A alleviates acute lung injury by inhibiting inflammation and epithelial barrier damages in lung and colon through PPAR-γ/RXR-α complex J. Adv. Res. 2024 60 183 200 37579917 10.1016/j.jare.2023.08.006 PMC11156707 Wang, J. et al. Forsythiaside A alleviates acute lung injury by inhibiting inflammation and epithelial barrier damages in lung and colon through PPAR-γ/RXR-α complex. J. Adv. Res. 60 , 183–200 (2024). 37579917 10.1016/j.jare.2023.08.006 PMC11156707

120. Capitão AMF An ancestral nuclear receptor couple, PPAR-RXR, is exploited by organotins Sci. Total Environ. 2021 797 149044 34303232 10.1016/j.scitotenv.2021.149044 Capitão, A. M. F. et al. An ancestral nuclear receptor couple, PPAR-RXR, is exploited by organotins. Sci. Total Environ. 797 , 149044 (2021). 34303232 10.1016/j.scitotenv.2021.149044

121. Chen L Modulation of nongenomic activation of PI3K signalling by tetramerization of N-terminally-cleaved RXRα Nat. Commun. 2017 8 16066 28714476 10.1038/ncomms16066 PMC5520057 Chen, L. et al. Modulation of nongenomic activation of PI3K signalling by tetramerization of N-terminally-cleaved RXRα. Nat. Commun. 8 , 16066 (2017). 28714476 10.1038/ncomms16066 PMC5520057

122. Kilu W Heterodimer formation with retinoic acid receptor RXRα modulates coactivator recruitment by peroxisome proliferator-activated receptor PPARγ J. Biol. Chem. 2021 297 100814 34081964 10.1016/j.jbc.2021.100814 PMC8258697 Kilu, W. et al. Heterodimer formation with retinoic acid receptor RXRα modulates coactivator recruitment by peroxisome proliferator-activated receptor PPARγ. J. Biol. Chem. 297 , 100814 (2021). 34081964 10.1016/j.jbc.2021.100814 PMC8258697

123. Moehren U Identification of androgen-selective androgen-response elements in the human aquaporin-5 and Rad9 genes Biochem J. 2008 411 679 686 18215141 10.1042/BJ20071352 Moehren, U. et al. Identification of androgen-selective androgen-response elements in the human aquaporin-5 and Rad9 genes. Biochem J. 411 , 679–686 (2008). 18215141 10.1042/BJ20071352

124. Petta I The interactome of the glucocorticoid receptor and its influence on the actions of glucocorticoids in combatting inflammatory and infectious diseases Microbiol Mol. Biol. Rev. 2016 80 495 522 27169854 10.1128/MMBR.00064-15 PMC4867367 Petta, I. et al. The interactome of the glucocorticoid receptor and its influence on the actions of glucocorticoids in combatting inflammatory and infectious diseases. Microbiol Mol. Biol. Rev. 80 , 495–522 (2016). 27169854 10.1128/MMBR.00064-15 PMC4867367

125. Hirayama, Y. & Sadar, M. D. Does increased expression of glucocorticoid receptor support application of antagonists to this receptor for the treatment of castration resistant prostate cancer? AME Med. J . 3 , (2018). 10.21037/amj.2018.06.02 PMC6124673 30198014

126. Bianchetti, L. et al. Alternative dimerization interfaces in the glucocorticoid receptor-α ligand binding domain. Biochim. Biophys. Acta Gen. Subj . 1862 , (2018). 10.1016/j.bbagen.2018.04.022 29723544

127. Dubey N The ESC/E(Z) complex, an effector of response to ovarian steroids, manifests an intrinsic difference in cells from women with premenstrual dysphoric disorder Mol. Psychiatry 2017 22 1172 1184 28044059 10.1038/mp.2016.229 PMC5495630 Dubey, N. et al. The ESC/E(Z) complex, an effector of response to ovarian steroids, manifests an intrinsic difference in cells from women with premenstrual dysphoric disorder. Mol. Psychiatry 22 , 1172–1184 (2017). 28044059 10.1038/mp.2016.229 PMC5495630

128. Pihlajamaa P Sahu B Jänne OA Determinants of receptor- and tissue-specific actions in androgen signaling Endocr. Rev. 2015 36 357 384 26052734 10.1210/er.2015-1034 Pihlajamaa, P., Sahu, B. & Jänne, O. A. Determinants of receptor- and tissue-specific actions in androgen signaling. Endocr. Rev. 36 , 357–384 (2015). 26052734 10.1210/er.2015-1034

129. Clarisse D Glucocorticoid receptor signaling: intricacies and therapeutic opportunities Trends Biochem. Sci. 2024 49 431 444 38429217 10.1016/j.tibs.2024.01.012 Clarisse, D. et al. Glucocorticoid receptor signaling: intricacies and therapeutic opportunities. Trends Biochem. Sci. 49 , 431–444 (2024). 38429217 10.1016/j.tibs.2024.01.012

130. Præstholm SM Correia CM Grøntved L Multifaceted control of GR signaling and its impact on hepatic transcriptional networks and metabolism Front. Endocrinol. (Lausanne) 2020 11 572981 33133019 10.3389/fendo.2020.572981 PMC7578419 Præstholm, S. M., Correia, C. M. & Grøntved, L. Multifaceted control of GR signaling and its impact on hepatic transcriptional networks and metabolism. Front. Endocrinol. (Lausanne) 11 , 572981 (2020). 33133019 10.3389/fendo.2020.572981 PMC7578419

131. Huss JM Garbacz WG Xie W Constitutive activities of estrogen-related receptors: Transcriptional regulation of metabolism by the ERR pathways in health and disease Biochim. Biophys. Acta Mol. Basis Dis. 2015 1852 1912 1927 10.1016/j.bbadis.2015.06.016 26115970 Huss, J. M., Garbacz, W. G. & Xie, W. Constitutive activities of estrogen-related receptors: Transcriptional regulation of metabolism by the ERR pathways in health and disease. Biochim. Biophys. Acta Mol. Basis Dis. 1852 , 1912–1927 (2015). 10.1016/j.bbadis.2015.06.016 26115970

132. Oka S PPARα-Sirt1 complex mediates cardiac hypertrophy and failure through suppression of the ERR transcriptional pathway Cell Metab. 2011 14 598 611 22055503 10.1016/j.cmet.2011.10.001 PMC3217210 Oka, S. et al. PPARα-Sirt1 complex mediates cardiac hypertrophy and failure through suppression of the ERR transcriptional pathway. Cell Metab. 14 , 598–611 (2011). 22055503 10.1016/j.cmet.2011.10.001 PMC3217210

133. Tzeng J An ideal PPAR response element bound to and activated by PPARα PLoS One 2015 10 e0134996 26241474 10.1371/journal.pone.0134996 PMC4524655 Tzeng, J. et al. An ideal PPAR response element bound to and activated by PPARα. PLoS One 10 , e0134996 (2015). 26241474 10.1371/journal.pone.0134996 PMC4524655

134. Fan W ERRγ promotes angiogenesis, mitochondrial biogenesis, and oxidative remodeling in PGC1α/β-deficient muscle Cell Rep. 2018 22 2521 2529 29514081 10.1016/j.celrep.2018.02.047 PMC5860878 Fan, W. et al. ERRγ promotes angiogenesis, mitochondrial biogenesis, and oxidative remodeling in PGC1α/β-deficient muscle. Cell Rep. 22 , 2521–2529 (2018). 29514081 10.1016/j.celrep.2018.02.047 PMC5860878

135. Wang XX Estrogen-related receptor agonism reverses mitochondrial dysfunction and inflammation in the aging kidney Am. J. Pathol. 2023 193 1969 1987 37717940 10.1016/j.ajpath.2023.07.008 PMC10734281 Wang, X. X. et al. Estrogen-related receptor agonism reverses mitochondrial dysfunction and inflammation in the aging kidney. Am. J. Pathol. 193 , 1969–1987 (2023). 37717940 10.1016/j.ajpath.2023.07.008 PMC10734281

136. Abe Y A TLR4/TRAF6-dependent signaling pathway mediates NCoR coactivator complex formation for inflammatory gene activation Proc. Natl. Acad. Sci. USA 2024 121 e2316104121 38165941 10.1073/pnas.2316104121 PMC10786282 Abe, Y. et al. A TLR4/TRAF6-dependent signaling pathway mediates NCoR coactivator complex formation for inflammatory gene activation. Proc. Natl. Acad. Sci. USA 121 , e2316104121 (2024). 38165941 10.1073/pnas.2316104121 PMC10786282

137. Mays SG Hercules D Ortlund EA Okafor CD The nuclear receptor LRH-1 discriminates between ligands using distinct allosteric signaling circuits Protein Sci. 2023 32 e4754 37572334 10.1002/pro.4754 PMC10510465 Mays, S. G., Hercules, D., Ortlund, E. A. & Okafor, C. D. The nuclear receptor LRH-1 discriminates between ligands using distinct allosteric signaling circuits. Protein Sci. 32 , e4754 (2023). 37572334 10.1002/pro.4754 PMC10510465

138. Hu C Heat shock proteins: Biological functions, pathological roles, and therapeutic opportunities MedComm (2020) 2022 3 e161 35928554 10.1002/mco2.161 PMC9345296 Hu, C. et al. Heat shock proteins: Biological functions, pathological roles, and therapeutic opportunities. MedComm (2020) 3 , e161 (2022). 35928554 10.1002/mco2.161 PMC9345296

139. Messner, E. A. et al. The androgen receptor in prostate cancer: Effect of structure, ligands and spliced variants on therapy. Biomedicines . 8 , (2020). 10.3390/biomedicines8100422 PMC7602609 33076388

140. Ni L Androgen induces a switch from cytoplasmic retention to nuclear import of the androgen receptor Mol. Cell Biol. 2013 33 4766 4778 24100013 10.1128/MCB.00647-13 PMC3889559 Ni, L. et al. Androgen induces a switch from cytoplasmic retention to nuclear import of the androgen receptor. Mol. Cell Biol. 33 , 4766–4778 (2013). 24100013 10.1128/MCB.00647-13 PMC3889559

141. Mohammad Nezhady MA Rivera JC Chemtob S Location bias as emerging paradigm in GPCR biology and drug discovery iScience 2020 23 101643 33103080 10.1016/j.isci.2020.101643 PMC7569339 Mohammad Nezhady, M. A., Rivera, J. C. & Chemtob, S. Location bias as emerging paradigm in GPCR biology and drug discovery. iScience 23 , 101643 (2020). 33103080 10.1016/j.isci.2020.101643 PMC7569339

142. Avilla MN The Ah receptor: Adaptive metabolism, ligand diversity, and the Xenokine Model Chem. Res. Toxicol. 2020 33 860 879 32259433 10.1021/acs.chemrestox.9b00476 PMC7175458 Avilla, M. N. et al. The Ah receptor: Adaptive metabolism, ligand diversity, and the Xenokine Model. Chem. Res. Toxicol. 33 , 860–879 (2020). 32259433 10.1021/acs.chemrestox.9b00476 PMC7175458

143. Liu K Zou C Qin B The association between nuclear receptors and ocular diseases Oncotarget 2017 8 27603 27615 28187442 10.18632/oncotarget.15178 PMC5432361 Liu, K., Zou, C. & Qin, B. The association between nuclear receptors and ocular diseases. Oncotarget 8 , 27603–27615 (2017). 28187442 10.18632/oncotarget.15178 PMC5432361

144. Park UH Kim EJ Um SJ A novel cytoplasmic adaptor for retinoic acid receptor (RAR) and thyroid receptor functions as a Derepressor of RAR in the absence of retinoic acid J. Biol. Chem. 2010 285 34269 34278 20736163 10.1074/jbc.M110.143008 PMC2962525 Park, U. H., Kim, E. J. & Um, S. J. A novel cytoplasmic adaptor for retinoic acid receptor (RAR) and thyroid receptor functions as a Derepressor of RAR in the absence of retinoic acid. J. Biol. Chem. 285 , 34269–34278 (2010). 20736163 10.1074/jbc.M110.143008 PMC2962525

145. Yu, T., Dube, N. & Okafor, C. D. Simulations reveal the flexible domain architecture of full-length nuclear receptor complexes. bioRxiv , (2024).

146. Fili N NDP52 activates nuclear myosin VI to enhance RNA polymerase II transcription Nat. Commun. 2017 8 1871 29187741 10.1038/s41467-017-02050-w PMC5707354 Fili, N. et al. NDP52 activates nuclear myosin VI to enhance RNA polymerase II transcription. Nat. Commun. 8 , 1871 (2017). 29187741 10.1038/s41467-017-02050-w PMC5707354

147. Dos Santos Á Autophagy receptor NDP52 alters DNA conformation to modulate RNA polymerase II transcription Nat. Commun. 2023 14 2855 37202403 10.1038/s41467-023-38572-9 PMC10195817 Dos Santos, Á et al. Autophagy receptor NDP52 alters DNA conformation to modulate RNA polymerase II transcription. Nat. Commun. 14 , 2855 (2023). 37202403 10.1038/s41467-023-38572-9 PMC10195817

148. Furuya, N. et al. NDP52 interacts with mitochondrial RNA poly(A) polymerase to promote mitophagy. EMBO Rep . 19 , (2018). 10.15252/embr.201846363 PMC6280801 30309841

149. Paakinaho V Johnson TA Presman DM Hager GL Glucocorticoid receptor quaternary structure drives chromatin occupancy and transcriptional outcome Genome Res 2019 29 1223 1234 31337711 10.1101/gr.244814.118 PMC6673716 Paakinaho, V., Johnson, T. A., Presman, D. M. & Hager, G. L. Glucocorticoid receptor quaternary structure drives chromatin occupancy and transcriptional outcome. Genome Res 29 , 1223–1234 (2019). 31337711 10.1101/gr.244814.118 PMC6673716

150. Schöne S Sequences flanking the core-binding site modulate glucocorticoid receptor structure and activity Nat. Commun. 2016 7 12621 27581526 10.1038/ncomms12621 PMC5025757 Schöne, S. et al. Sequences flanking the core-binding site modulate glucocorticoid receptor structure and activity. Nat. Commun. 7 , 12621 (2016). 27581526 10.1038/ncomms12621 PMC5025757

151. Jiang L Structural characterization of the DNA binding mechanism of retinoic acid-related orphan receptor gamma Structure 2024 32 467 475.e463 38309263 10.1016/j.str.2024.01.004 Jiang, L. et al. Structural characterization of the DNA binding mechanism of retinoic acid-related orphan receptor gamma. Structure 32 , 467–475.e463 (2024). 38309263 10.1016/j.str.2024.01.004

152. Johnson DR NuRD complex component Mi-2beta binds to and represses RORgamma-mediated transcriptional activation Biochem. Biophys. Res Commun. 2004 318 714 718 15144897 10.1016/j.bbrc.2004.04.087 Johnson, D. R. et al. NuRD complex component Mi-2beta binds to and represses RORgamma-mediated transcriptional activation. Biochem. Biophys. Res Commun. 318 , 714–718 (2004). 15144897 10.1016/j.bbrc.2004.04.087

153. Jenniskens M Cholestatic liver (dys)function during sepsis and other critical illnesses Intensive Care Med 2016 42 16 27 26392257 10.1007/s00134-015-4054-0 Jenniskens, M. et al. Cholestatic liver (dys)function during sepsis and other critical illnesses. Intensive Care Med . 42 , 16–27 (2016). 26392257 10.1007/s00134-015-4054-0

154. Zheng Y COX-2 mediates tumor-stromal prolactin signaling to initiate tumorigenesis Proc. Natl. Acad. Sci. USA 2019 116 5223 5232 30819896 10.1073/pnas.1819303116 PMC6431196 Zheng, Y. et al. COX-2 mediates tumor-stromal prolactin signaling to initiate tumorigenesis. Proc. Natl. Acad. Sci. USA 116 , 5223–5232 (2019). 30819896 10.1073/pnas.1819303116 PMC6431196

155. Dauwe, Y. et al. Steatosis and metabolic disorders associated with synergistic activation of the CAR/RXR heterodimer by pesticides. Cells . 12 , (2023). 10.3390/cells12081201 PMC10137125 37190111

156. Huber AD Chen T A new mode of inhibition eLife 2024 13 e101446 39158026 10.7554/eLife.101446 PMC11333039 Huber, A. D. & Chen, T. A new mode of inhibition. eLife 13 , e101446 (2024). 39158026 10.7554/eLife.101446 PMC11333039

157. Jaladanki CK Virtual screening of potentially endocrine-disrupting chemicals against nuclear receptors and its application to identify PPARγ-bound fatty acids Arch. Toxicol. 2021 95 355 374 32909075 10.1007/s00204-020-02897-x PMC7811525 Jaladanki, C. K. et al. Virtual screening of potentially endocrine-disrupting chemicals against nuclear receptors and its application to identify PPARγ-bound fatty acids. Arch. Toxicol. 95 , 355–374 (2021). 32909075 10.1007/s00204-020-02897-x PMC7811525

158. Martens, N. et al. Activation of liver X receptors and peroxisome proliferator-activated receptors by lipid extracts of Brown Seaweeds: A potential application in Alzheimer’s disease? Nutrients . 15 , (2023). 10.3390/nu15133004 PMC10347067 37447330

159. Tan H Structures of endocrine-disrupting chemicals correlate with the activation of 12 classic nuclear receptors Environ. Sci. Technol. 2021 55 16552 16562 34859678 10.1021/acs.est.1c04997 Tan, H. et al. Structures of endocrine-disrupting chemicals correlate with the activation of 12 classic nuclear receptors. Environ. Sci. Technol. 55 , 16552–16562 (2021). 34859678 10.1021/acs.est.1c04997

160. Blackburn CMR Myeloid-associated lipin-1 transcriptional co-regulatory activity is atheroprotective Atherosclerosis 2021 330 76 84 34256308 10.1016/j.atherosclerosis.2021.06.927 PMC8328963 Blackburn, C. M. R. et al. Myeloid-associated lipin-1 transcriptional co-regulatory activity is atheroprotective. Atherosclerosis 330 , 76–84 (2021). 34256308 10.1016/j.atherosclerosis.2021.06.927 PMC8328963

161. Kumar R Lee JC Bolen DW Thompson EB The conformation of the glucocorticoid receptor af1/tau1 domain induced by osmolyte binds co-regulatory proteins J. Biol. Chem. 2001 276 18146 18152 11279138 10.1074/jbc.M100825200 Kumar, R., Lee, J. C., Bolen, D. W. & Thompson, E. B. The conformation of the glucocorticoid receptor af1/tau1 domain induced by osmolyte binds co-regulatory proteins. J. Biol. Chem. 276 , 18146–18152 (2001). 11279138 10.1074/jbc.M100825200

162. Hosseinzadeh L The androgen receptor interacts with GATA3 to transcriptionally regulate a luminal epithelial cell phenotype in breast cancer Genome Biol. 2024 25 44 38317241 10.1186/s13059-023-03161-y PMC10840202 Hosseinzadeh, L. et al. The androgen receptor interacts with GATA3 to transcriptionally regulate a luminal epithelial cell phenotype in breast cancer. Genome Biol. 25 , 44 (2024). 38317241 10.1186/s13059-023-03161-y PMC10840202

163. Talukdar PD Chatterji U Transcriptional co-activators: emerging roles in signaling pathways and potential therapeutic targets for diseases Signal Transduct. Target Ther. 2023 8 427 37953273 10.1038/s41392-023-01651-w PMC10641101 Talukdar, P. D. & Chatterji, U. Transcriptional co-activators: emerging roles in signaling pathways and potential therapeutic targets for diseases. Signal Transduct. Target Ther. 8 , 427 (2023). 37953273 10.1038/s41392-023-01651-w PMC10641101

164. Bahl S Seto E Regulation of histone deacetylase activities and functions by phosphorylation and its physiological relevance Cell. Mol. Life Sci. 2021 78 427 445 32683534 10.1007/s00018-020-03599-4 PMC7854769 Bahl, S. & Seto, E. Regulation of histone deacetylase activities and functions by phosphorylation and its physiological relevance. Cell. Mol. Life Sci. 78 , 427–445 (2021). 32683534 10.1007/s00018-020-03599-4 PMC7854769

165. Corso-Díaz X Co-activator candidate interactions for orphan nuclear receptor NR2E1 BMC Genomics 2016 17 832 27782803 10.1186/s12864-016-3173-5 PMC5080790 Corso-Díaz, X. et al. Co-activator candidate interactions for orphan nuclear receptor NR2E1. BMC Genomics 17 , 832 (2016). 27782803 10.1186/s12864-016-3173-5 PMC5080790

166. Perez-Mockus G The Drosophila ecdysone receptor promotes or suppresses proliferation according to ligand level Dev. Cell. 2023 58 2128 2139.e2124 37769663 10.1016/j.devcel.2023.08.032 PMC7615657 Perez-Mockus, G. et al. The Drosophila ecdysone receptor promotes or suppresses proliferation according to ligand level. Dev. Cell. 58 , 2128–2139.e2124 (2023). 37769663 10.1016/j.devcel.2023.08.032 PMC7615657

167. Akiyama, T., Raftery, L. A. & Wharton, K. A. Bone morphogenetic protein signaling: the pathway and its regulation. Genetics . 226 , (2023). 10.1093/genetics/iyad200 PMC10847725 38124338

168. Bure IV Nemtsova MV Kuznetsova EB Histone Modifications and Non-Coding RNAs: Mutual Epigenetic Regulation and Role in Pathogenesis Int. J. Mol. Sci. 2022 23 5801 35628612 10.3390/ijms23105801 PMC9146199 Bure, I. V., Nemtsova, M. V. & Kuznetsova, E. B. Histone Modifications and Non-Coding RNAs: Mutual Epigenetic Regulation and Role in Pathogenesis. Int. J. Mol. Sci. 23 , 5801 (2022). 35628612 10.3390/ijms23105801 PMC9146199

169. Kumar, S. & Mohapatra, T. Epigenetic modifications in genome help remembering the stress tolerance strategy adopted by the plant. FBL . 29 , (2024). 10.31083/j.fbl2903126 38538276

170. Flora GD Non-genomic effects of the Pregnane X receptor negatively regulate platelet functions, thrombosis and haemostasis Sci. Rep. 2019 9 17210 31748641 10.1038/s41598-019-53218-x PMC6868193 Flora, G. D. et al. Non-genomic effects of the Pregnane X receptor negatively regulate platelet functions, thrombosis and haemostasis. Sci. Rep. 9 , 17210 (2019). 31748641 10.1038/s41598-019-53218-x PMC6868193

171. Burgermeister E Mitogen-activated protein kinase and nuclear hormone receptor crosstalk in cancer immunotherapy Int. J. Mol. Sci. 2023 24 13661 37686465 10.3390/ijms241713661 PMC10488039 Burgermeister, E. Mitogen-activated protein kinase and nuclear hormone receptor crosstalk in cancer immunotherapy. Int. J. Mol. Sci. 24 , 13661 (2023). 37686465 10.3390/ijms241713661 PMC10488039

172. Großkopf H Non-genomic AhR-signaling modulates the immune response in endotoxin-activated macrophages after activation by the environmental stressor BaP Front. Immunol. 2021 12 620270 33868237 10.3389/fimmu.2021.620270 PMC8045971 Großkopf, H. et al. Non-genomic AhR-signaling modulates the immune response in endotoxin-activated macrophages after activation by the environmental stressor BaP. Front. Immunol. 12 , 620270 (2021). 33868237 10.3389/fimmu.2021.620270 PMC8045971

173. Gourdy P Estrogen receptor subcellular localization and cardiometabolism Mol. Metab. 2018 15 56 69 29807870 10.1016/j.molmet.2018.05.009 PMC6066739 Gourdy, P. et al. Estrogen receptor subcellular localization and cardiometabolism. Mol. Metab. 15 , 56–69 (2018). 29807870 10.1016/j.molmet.2018.05.009 PMC6066739

174. Zhu F The orphan receptor Nur77 binds cytoplasmic LPS to activate the non-canonical NLRP3 inflammasome Immunity 2023 56 753 767.e758 37001519 10.1016/j.immuni.2023.03.003 Zhu, F. et al. The orphan receptor Nur77 binds cytoplasmic LPS to activate the non-canonical NLRP3 inflammasome. Immunity 56 , 753–767.e758 (2023). 37001519 10.1016/j.immuni.2023.03.003

175. Ma YL Semaglutide ameliorates cardiac remodeling in male mice by optimizing energy substrate utilization through the Creb5/NR4a1 axis Nat. Commun. 2024 15 4757 38834564 10.1038/s41467-024-48970-2 PMC11150406 Ma, Y. L. et al. Semaglutide ameliorates cardiac remodeling in male mice by optimizing energy substrate utilization through the Creb5/NR4a1 axis. Nat. Commun. 15 , 4757 (2024). 38834564 10.1038/s41467-024-48970-2 PMC11150406

176. Rehman SU Identification of two novel isoforms of mouse NUR77 lacking N-terminal domains IUBMB Life 2017 69 106 114 28111880 10.1002/iub.1605 Rehman, S. U. et al. Identification of two novel isoforms of mouse NUR77 lacking N-terminal domains. IUBMB Life 69 , 106–114 (2017). 28111880 10.1002/iub.1605

177. Nyati KK TLR4-induced NF-κB and MAPK signaling regulate the IL-6 mRNA stabilizing protein Arid5a NAR 2017 45 2687 2703 28168301 10.1093/nar/gkx064 PMC5389518 Nyati, K. K. et al. TLR4-induced NF-κB and MAPK signaling regulate the IL-6 mRNA stabilizing protein Arid5a. NAR 45 , 2687–2703 (2017). 28168301 10.1093/nar/gkx064 PMC5389518

178. Santos RS Activation of estrogen receptor alpha induces beiging of adipocytes Mol. Metab. 2018 18 51 59 30270132 10.1016/j.molmet.2018.09.002 PMC6309577 Santos, R. S. et al. Activation of estrogen receptor alpha induces beiging of adipocytes. Mol. Metab. 18 , 51–59 (2018). 30270132 10.1016/j.molmet.2018.09.002 PMC6309577

179. Bennett L Glucocorticoid receptor (GR) activation is associated with increased cAMP/PKA signaling in castration-resistant prostate cancer Mol. Cancer Ther. 2024 23 552 563 38030378 10.1158/1535-7163.MCT-22-0479 PMC10985475 Bennett, L. et al. Glucocorticoid receptor (GR) activation is associated with increased cAMP/PKA signaling in castration-resistant prostate cancer. Mol. Cancer Ther. 23 , 552–563 (2024). 38030378 10.1158/1535-7163.MCT-22-0479 PMC10985475

180. Jung K Farnesoid X receptor activation impairs liver progenitor cell-mediated liver regeneration via the PTEN-PI3K-AKT-mTOR axis in zebrafish Hepatology 2021 74 397 410 33314176 10.1002/hep.31679 PMC8605479 Jung, K. et al. Farnesoid X receptor activation impairs liver progenitor cell-mediated liver regeneration via the PTEN-PI3K-AKT-mTOR axis in zebrafish. Hepatology 74 , 397–410 (2021). 33314176 10.1002/hep.31679 PMC8605479

181. Li X YAP inhibits ERα and ER(+) breast cancer growth by disrupting a TEAD-ERα signaling axis Nat. Commun. 2022 13 3075 35654829 10.1038/s41467-022-30831-5 PMC9163075 Li, X. et al. YAP inhibits ERα and ER(+) breast cancer growth by disrupting a TEAD-ERα signaling axis. Nat. Commun. 13 , 3075 (2022). 35654829 10.1038/s41467-022-30831-5 PMC9163075

182. Leung YK The loss of an orphan nuclear receptor NR2E3 augments Wnt/β-catenin signaling via epigenetic dysregulation that enhances Sp1-β catenin-p300 interactions in hepatocellular carcinoma Adv. Sci. (Weinh.) 2024 11 e2308539 38790135 10.1002/advs.202308539 PMC11304255 Leung, Y. K. et al. The loss of an orphan nuclear receptor NR2E3 augments Wnt/β-catenin signaling via epigenetic dysregulation that enhances Sp1-β catenin-p300 interactions in hepatocellular carcinoma. Adv. Sci. (Weinh.) 11 , e2308539 (2024). 38790135 10.1002/advs.202308539 PMC11304255

183. Hori T Nuclear receptor CAR suppresses GADD45B-p38 MAPK signaling to promote phenobarbital-induced proliferation in mouse liver Mol. Cancer Res. 2018 16 1309 1318 29716964 10.1158/1541-7786.MCR-18-0118 Hori, T. et al. Nuclear receptor CAR suppresses GADD45B-p38 MAPK signaling to promote phenobarbital-induced proliferation in mouse liver. Mol. Cancer Res. 16 , 1309–1318 (2018). 29716964 10.1158/1541-7786.MCR-18-0118

184. Tao Y Nr4a1 promotes renal interstitial fibrosis by regulating the p38 MAPK phosphorylation Mol. Med. 2023 29 63 37161357 10.1186/s10020-023-00657-y PMC10169452 Tao, Y. et al. Nr4a1 promotes renal interstitial fibrosis by regulating the p38 MAPK phosphorylation. Mol. Med. 29 , 63 (2023). 37161357 10.1186/s10020-023-00657-y PMC10169452

185. Ashraf S Hegazy YK Harmancey R Nuclear receptor subfamily 4 group A member 2 inhibits activation of ERK signaling and cell growth in response to β-adrenergic stimulation in adult rat cardiomyocytes Am. J. Physiol. Cell Physiol. 2019 317 C513 c524 31188636 10.1152/ajpcell.00526.2018 PMC6766613 Ashraf, S., Hegazy, Y. K. & Harmancey, R. Nuclear receptor subfamily 4 group A member 2 inhibits activation of ERK signaling and cell growth in response to β-adrenergic stimulation in adult rat cardiomyocytes. Am. J. Physiol. Cell Physiol. 317 , C513–c524 (2019). 31188636 10.1152/ajpcell.00526.2018 PMC6766613

186. Romero-Martínez, B. S. et al. Estrogenic modulation of ionic channels, pumps and exchangers in airway smooth muscle. Int. J. Mol. Sci . 24 , (2023). 10.3390/ijms24097879 PMC10178541 37175587

187. de Hoog E Lukewich MK Spencer GE Retinoic acid inhibits neuronal voltage-gated calcium channels Cell Calcium 2018 72 51 61 29748133 10.1016/j.ceca.2018.02.001 de Hoog, E., Lukewich, M. K. & Spencer, G. E. Retinoic acid inhibits neuronal voltage-gated calcium channels. Cell Calcium 72 , 51–61 (2018). 29748133 10.1016/j.ceca.2018.02.001

188. Sahoo N Intracellular hemin is a potent inhibitor of the voltage-gated potassium channel Kv10.1 Sci. Rep. 2022 12 14645 36030326 10.1038/s41598-022-18975-2 PMC9420133 Sahoo, N. et al. Intracellular hemin is a potent inhibitor of the voltage-gated potassium channel Kv10.1. Sci. Rep. 12 , 14645 (2022). 36030326 10.1038/s41598-022-18975-2 PMC9420133

189. Unsworth AJ Flora GD Gibbins JM Non-genomic effects of nuclear receptors: insights from the anucleate platelet Cardiovasc. Res. 2018 114 645 655 29452349 10.1093/cvr/cvy044 PMC5915957 Unsworth, A. J., Flora, G. D. & Gibbins, J. M. Non-genomic effects of nuclear receptors: insights from the anucleate platelet. Cardiovasc. Res. 114 , 645–655 (2018). 29452349 10.1093/cvr/cvy044 PMC5915957

190. Nuñez FJ Glucocorticoids rapidly activate cAMP production via G(αs) to initiate non-genomic signaling that contributes to one-third of their canonical genomic effects FASEB J. 2020 34 2882 2895 31908022 10.1096/fj.201902521R PMC7027561 Nuñez, F. J. et al. Glucocorticoids rapidly activate cAMP production via G(αs) to initiate non-genomic signaling that contributes to one-third of their canonical genomic effects. FASEB J. 34 , 2882–2895 (2020). 31908022 10.1096/fj.201902521R PMC7027561

191. Chen L Wu L Zhu L Zhao Y Overview of the structure-based non-genomic effects of the nuclear receptor RXRα Cell. Mol. Biol. Lett. 2018 23 36 30093910 10.1186/s11658-018-0103-3 PMC6080560 Chen, L., Wu, L., Zhu, L. & Zhao, Y. Overview of the structure-based non-genomic effects of the nuclear receptor RXRα. Cell. Mol. Biol. Lett. 23 , 36 (2018). 30093910 10.1186/s11658-018-0103-3 PMC6080560

192. Liu Y Effect of retinoid X receptor-α nuclear export inhibition on apoptosis of neurons in vivo and in vitro Mol. Med. Rep. 2017 16 2037 2044 28627642 10.3892/mmr.2017.6766 Liu, Y. et al. Effect of retinoid X receptor-α nuclear export inhibition on apoptosis of neurons in vivo and in vitro. Mol. Med. Rep. 16 , 2037–2044 (2017). 28627642 10.3892/mmr.2017.6766

193. Xie CK Sulindac (K-80003) with nab-paclitaxel and gemcitabine overcomes drug-resistant pancreatic cancer Mol. Cancer 2024 23 215 39350121 10.1186/s12943-024-02128-2 PMC11441089 Xie, C. K. et al. Sulindac (K-80003) with nab-paclitaxel and gemcitabine overcomes drug-resistant pancreatic cancer. Mol. Cancer 23 , 215 (2024). 39350121 10.1186/s12943-024-02128-2 PMC11441089

194. Li H Oroxylin A, a natural compound, mitigates the negative effects of TNFα-treated acute myelogenous leukemia cells Carcinogenesis 2018 39 1292 1303 29346508 10.1093/carcin/bgy004 Li, H. et al. Oroxylin A, a natural compound, mitigates the negative effects of TNFα-treated acute myelogenous leukemia cells. Carcinogenesis 39 , 1292–1303 (2018). 29346508 10.1093/carcin/bgy004

195. Abdoul-Azize S Glucocorticoids paradoxically promote steroid resistance in B cell acute lymphoblastic leukemia through CXCR4/PLC signaling Nat. Commun. 2024 15 4557 38811530 10.1038/s41467-024-48818-9 PMC11136999 Abdoul-Azize, S. et al. Glucocorticoids paradoxically promote steroid resistance in B cell acute lymphoblastic leukemia through CXCR4/PLC signaling. Nat. Commun. 15 , 4557 (2024). 38811530 10.1038/s41467-024-48818-9 PMC11136999

196. Zhou F A narrative review of the role of glucocorticoid receptors in prostate cancer: developments in last 5 years Transl. Androl. Urol. 2022 11 1189 1199 36092840 10.21037/tau-22-501 PMC9459548 Zhou, F. et al. A narrative review of the role of glucocorticoid receptors in prostate cancer: developments in last 5 years. Transl. Androl. Urol. 11 , 1189–1199 (2022). 36092840 10.21037/tau-22-501 PMC9459548

197. Ehrchen JM Roth J Barczyk-Kahlert K More than suppression: Glucocorticoid action on monocytes and macrophages Front. Immunol. 2019 10 2028 31507614 10.3389/fimmu.2019.02028 PMC6718555 Ehrchen, J. M., Roth, J. & Barczyk-Kahlert, K. More than suppression: Glucocorticoid action on monocytes and macrophages. Front. Immunol. 10 , 2028 (2019). 31507614 10.3389/fimmu.2019.02028 PMC6718555

198. Ma Y Huang Y Xu G New insights into the mucosal immune pathogenesis of IgA nephropathy from the perspective of COVID-19 vaccination QJM 2023 116 181 195 36592052 10.1093/qjmed/hcac287 Ma, Y., Huang, Y. & Xu, G. New insights into the mucosal immune pathogenesis of IgA nephropathy from the perspective of COVID-19 vaccination. QJM 116 , 181–195 (2023). 36592052 10.1093/qjmed/hcac287

199. Panettieri RA Non-genomic effects of glucocorticoids: An updated view Trends Pharmacol. Sci. 2019 40 38 49 30497693 10.1016/j.tips.2018.11.002 PMC7106476 Panettieri, R. A. et al. Non-genomic effects of glucocorticoids: An updated view. Trends Pharmacol. Sci. 40 , 38–49 (2019). 30497693 10.1016/j.tips.2018.11.002 PMC7106476

200. Maczewsky J Kaiser J Krippeit-Drews P Drews G Approved LXR agonists exert unspecific effects on pancreatic β-cell function Endocrine 2020 68 526 535 32146655 10.1007/s12020-020-02241-4 PMC7308254 Maczewsky, J., Kaiser, J., Krippeit-Drews, P. & Drews, G. Approved LXR agonists exert unspecific effects on pancreatic β-cell function. Endocrine 68 , 526–535 (2020). 32146655 10.1007/s12020-020-02241-4 PMC7308254

201. Kierans SJ Hypoxia induces a glycolytic complex in intestinal epithelial cells independent of HIF-1-driven glycolytic gene expression Proc. Natl. Acad. Sci. USA 2023 120 e2208117120 37603756 10.1073/pnas.2208117120 PMC10469334 Kierans, S. J. et al. Hypoxia induces a glycolytic complex in intestinal epithelial cells independent of HIF-1-driven glycolytic gene expression. Proc. Natl. Acad. Sci. USA 120 , e2208117120 (2023). 37603756 10.1073/pnas.2208117120 PMC10469334

202. Ambhore NS Differential estrogen-receptor activation regulates extracellular matrix deposition in human airway smooth muscle remodeling via NF-κB pathway FASEB J. 2019 33 13935 13950 31638834 10.1096/fj.201901340R PMC6894056 Ambhore, N. S. et al. Differential estrogen-receptor activation regulates extracellular matrix deposition in human airway smooth muscle remodeling via NF-κB pathway. FASEB J. 33 , 13935–13950 (2019). 31638834 10.1096/fj.201901340R PMC6894056

203. Roşca, A. E. et al. Effects of exogenous androgens on platelet activity and their thrombogenic potential in supraphysiological administration: A literature review. J Clin Med . 10 , (2021). 10.3390/jcm10010147 PMC7795962 33406783

204. Sesti F Late-onset hypogonadism: Reductio ad absurdum of the cardiovascular risk-benefit of testosterone replacement therapy Andrology 2020 8 1614 1627 32737921 10.1111/andr.12876 Sesti, F. et al. Late-onset hypogonadism: Reductio ad absurdum of the cardiovascular risk-benefit of testosterone replacement therapy. Andrology 8 , 1614–1627 (2020). 32737921 10.1111/andr.12876

205. Li S Experimental arterial thrombosis regulated by androgen and its receptor via modulation of platelet activation Thromb. Res. 2007 121 127 134 17451792 10.1016/j.thromres.2007.03.008 Li, S. et al. Experimental arterial thrombosis regulated by androgen and its receptor via modulation of platelet activation. Thromb. Res. 121 , 127–134 (2007). 17451792 10.1016/j.thromres.2007.03.008

206. Chang S Platelet aggregation in Klinefelter syndrome is not aggravated by testosterone replacement therapy: A longitudinal follow-up study Andrology 2023 11 456 463 36300871 10.1111/andr.13330 Chang, S. et al. Platelet aggregation in Klinefelter syndrome is not aggravated by testosterone replacement therapy: A longitudinal follow-up study. Andrology 11 , 456–463 (2023). 36300871 10.1111/andr.13330

207. Unsworth AJ RXR ligands negatively regulate thrombosis and hemostasis Atertio. Thromb. Vasc. Biol. 2017 37 812 822 10.1161/ATVBAHA.117.309207 PMC5405776 28254816 Unsworth, A. J. et al. RXR ligands negatively regulate thrombosis and hemostasis. Atertio. Thromb. Vasc. Biol. 37 , 812–822 (2017). 10.1161/ATVBAHA.117.309207 PMC5405776 28254816

208. Grover SP Bergmeier W Mackman N Platelet signaling pathways and new inhibitors Atertio. Thromb. Vasc. Biol. 2018 38 e28 e35 10.1161/ATVBAHA.118.310224 PMC5989728 29563117 Grover, S. P., Bergmeier, W. & Mackman, N. Platelet signaling pathways and new inhibitors. Atertio. Thromb. Vasc. Biol. 38 , e28–e35 (2018). 10.1161/ATVBAHA.118.310224 PMC5989728 29563117

209. Moraes LA Farnesoid X receptor and its ligands inhibit the function of platelets Arterioscler. Thromb. Vasc. Biol. 2016 36 2324 2333 27758768 10.1161/ATVBAHA.116.308093 PMC5144997 Moraes, L. A. et al. Farnesoid X receptor and its ligands inhibit the function of platelets. Arterioscler. Thromb. Vasc. Biol. 36 , 2324–2333 (2016). 27758768 10.1161/ATVBAHA.116.308093 PMC5144997

210. Zhou X Mechanism of bile acid in regulating platelet function and thrombotic diseases Adv. Sci. (Weinh.) 2024 11 e2401683 38922767 10.1002/advs.202401683 PMC11348205 Zhou, X. et al. Mechanism of bile acid in regulating platelet function and thrombotic diseases. Adv. Sci. (Weinh.) 11 , e2401683 (2024). 38922767 10.1002/advs.202401683 PMC11348205

211. Unsworth AJ Farnesoid X receptor and liver X receptor ligands initiate formation of coated platelets Arterioscler. Thromb. Vasc. Biol. 2017 37 1482 1493 28619996 10.1161/ATVBAHA.117.309135 PMC5526435 Unsworth, A. J. et al. Farnesoid X receptor and liver X receptor ligands initiate formation of coated platelets. Arterioscler. Thromb. Vasc. Biol. 37 , 1482–1493 (2017). 28619996 10.1161/ATVBAHA.117.309135 PMC5526435

212. Topalov NN Two types of procoagulant platelets are formed upon physiological activation and are controlled by integrin α(IIb)β(3) Arterioscler. Thromb. Vasc. Biol. 2012 32 2475 2483 22837472 10.1161/ATVBAHA.112.253765 Topalov, N. N. et al. Two types of procoagulant platelets are formed upon physiological activation and are controlled by integrin α(IIb)β(3). Arterioscler. Thromb. Vasc. Biol. 32 , 2475–2483 (2012). 22837472 10.1161/ATVBAHA.112.253765

213. Ferreira JP Fenofibrate and heart failure outcomes in patients with type 2 diabetes: Analysis from ACCORD Diab. Care 2022 45 1584 1591 10.2337/dc21-1977 PMC9274224 35320363 Ferreira, J. P. et al. Fenofibrate and heart failure outcomes in patients with type 2 diabetes: Analysis from ACCORD. Diab. Care 45 , 1584–1591 (2022). 10.2337/dc21-1977 PMC9274224 35320363

214. Bye AP Unsworth AJ Gibbins JM Platelet signaling: A complex interplay between inhibitory and activatory networks J. Thromb. Haemost. 2016 14 918 930 26929147 10.1111/jth.13302 PMC4879507 Bye, A. P., Unsworth, A. J. & Gibbins, J. M. Platelet signaling: A complex interplay between inhibitory and activatory networks. J. Thromb. Haemost. 14 , 918–930 (2016). 26929147 10.1111/jth.13302 PMC4879507

215. Ali FY Antiplatelet actions of statins and fibrates are mediated by PPARs Arterioscler. Thromb. Vasc. Biol. 2009 29 706 711 19150877 10.1161/ATVBAHA.108.183160 Ali, F. Y. et al. Antiplatelet actions of statins and fibrates are mediated by PPARs. Arterioscler. Thromb. Vasc. Biol. 29 , 706–711 (2009). 19150877 10.1161/ATVBAHA.108.183160

216. Al Tanoury Z Piskunov A Rochette-Egly C Vitamin A and retinoid signaling: genomic and nongenomic effects J. Lipid Res 2013 54 1761 1775 23440512 10.1194/jlr.R030833 PMC3679380 Al Tanoury, Z., Piskunov, A. & Rochette-Egly, C. Vitamin A and retinoid signaling: genomic and nongenomic effects. J. Lipid Res 54 , 1761–1775 (2013). 23440512 10.1194/jlr.R030833 PMC3679380

217. Yu Z ATRA-mediated-crosstalk between stellate cells and Kupffer cells inhibits autophagy and promotes NLRP3 activation in acute liver injury Cell. Signal. 2022 93 110304 35278669 10.1016/j.cellsig.2022.110304 Yu, Z. et al. ATRA-mediated-crosstalk between stellate cells and Kupffer cells inhibits autophagy and promotes NLRP3 activation in acute liver injury. Cell. Signal. 93 , 110304 (2022). 35278669 10.1016/j.cellsig.2022.110304

218. Harding EK Ferron L Zamponi GW RAR-alpha: Creator, protector, and tormentor Neuron 2022 110 4033 4035 36549266 10.1016/j.neuron.2022.10.039 Harding, E. K., Ferron, L. & Zamponi, G. W. RAR-alpha: Creator, protector, and tormentor. Neuron 110 , 4033–4035 (2022). 36549266 10.1016/j.neuron.2022.10.039

219. Sengör B Effects of acitretin on spermatogenesis of rats J. Eur. Acad. Dermatol. Venereol. 2006 20 689 692 16836496 10.1111/j.1468-3083.2006.01573.x Sengör, B. et al. Effects of acitretin on spermatogenesis of rats. J. Eur. Acad. Dermatol. Venereol. 20 , 689–692 (2006). 16836496 10.1111/j.1468-3083.2006.01573.x

220. Zhu L Doyle TJ Kim KH Retinoic acid modulates the subcellular localization of small ubiquitin-related modifier-2/3 (SUMO-2/3) in the testis J. Androl. 2010 31 406 418 20075418 10.2164/jandrol.109.008763 Zhu, L., Doyle, T. J. & Kim, K. H. Retinoic acid modulates the subcellular localization of small ubiquitin-related modifier-2/3 (SUMO-2/3) in the testis. J. Androl. 31 , 406–418 (2010). 20075418 10.2164/jandrol.109.008763

221. Walker SE Retinoid X receptor α downregulation is required for tail and caudal spinal cord regeneration in the adult newt Neural Regen. Res. 2018 13 1036 1045 29926831 10.4103/1673-5374.233447 PMC6022477 Walker, S. E. et al. Retinoid X receptor α downregulation is required for tail and caudal spinal cord regeneration in the adult newt. Neural Regen. Res. 13 , 1036–1045 (2018). 29926831 10.4103/1673-5374.233447 PMC6022477

222. Chen L Lau AG Sarti F Synaptic retinoic acid signaling and homeostatic synaptic plasticity Neuropharmacology 2014 78 3 12 23270606 10.1016/j.neuropharm.2012.12.004 PMC3884035 Chen, L., Lau, A. G. & Sarti, F. Synaptic retinoic acid signaling and homeostatic synaptic plasticity. Neuropharmacology 78 , 3–12 (2014). 23270606 10.1016/j.neuropharm.2012.12.004 PMC3884035

223. Park E Lau AG Arendt KL Chen L FMRP interacts with RARα in synaptic retinoic acid signaling and homeostatic synaptic plasticity Int. J. Mol. Sci. 2021 22 6579 34205274 10.3390/ijms22126579 PMC8235556 Park, E., Lau, A. G., Arendt, K. L. & Chen, L. FMRP interacts with RARα in synaptic retinoic acid signaling and homeostatic synaptic plasticity. Int. J. Mol. Sci. 22 , 6579 (2021). 34205274 10.3390/ijms22126579 PMC8235556

224. Khatib, T., Muller, B. & McCaffery, P. Vol. 2524 197-207 (2022). 10.1007/978-1-0716-2453-1_15 35821473

225. Zhong LR Retinoic acid receptor RARα-dependent synaptic signaling mediates homeostatic synaptic plasticity at the inhibitory synapses of mouse visual cortex J. Neurosci. 2018 38 10454 10466 30355624 10.1523/JNEUROSCI.1133-18.2018 PMC6284108 Zhong, L. R. et al. Retinoic acid receptor RARα-dependent synaptic signaling mediates homeostatic synaptic plasticity at the inhibitory synapses of mouse visual cortex. J. Neurosci. 38 , 10454–10466 (2018). 30355624 10.1523/JNEUROSCI.1133-18.2018 PMC6284108

226. Rossillo M Ringstad N Development of specialized sensory neurons engages a nuclear receptor required for functional plasticity Genes Dev. 2020 34 1666 1679 33184226 10.1101/gad.342212.120 PMC7706712 Rossillo, M. & Ringstad, N. Development of specialized sensory neurons engages a nuclear receptor required for functional plasticity. Genes Dev. 34 , 1666–1679 (2020). 33184226 10.1101/gad.342212.120 PMC7706712

227. Riedl J Fieseler C Zimmer M Tyraminergic corollary discharge filters reafferent perception in a chemosensory neuron Curr. Biol. 2022 32 3048 3058.e3046 35690069 10.1016/j.cub.2022.05.051 Riedl, J., Fieseler, C. & Zimmer, M. Tyraminergic corollary discharge filters reafferent perception in a chemosensory neuron. Curr. Biol. 32 , 3048–3058.e3046 (2022). 35690069 10.1016/j.cub.2022.05.051

228. Brandt J A single gene target of an ETS-family transcription factor determines neuronal CO2-chemosensitivity PLoS One 2012 7 e34014 22479504 10.1371/journal.pone.0034014 PMC3315506 Brandt, J. et al. A single gene target of an ETS-family transcription factor determines neuronal CO2-chemosensitivity. PLoS One 7 , e34014 (2012). 22479504 10.1371/journal.pone.0034014 PMC3315506

229. Smith, E., Martinez-Velazquez, L. & Ringstad, N. A chemoreceptor that detects molecular carbon dioxide. J. Biol. Chem . 288 , (2013). 10.1074/jbc.M113.517367 PMC3873563 24240097

230. Lee, Y. H. et al. Hepatic MIR20B promotes nonalcoholic fatty liver disease by suppressing PPARA. Elife . 10 , (2021). 10.7554/eLife.70472 PMC8758141 34964438

231. Lee MC Tributyltin affects retinoid X receptor-mediated lipid metabolism in the marine Rotifer Brachionus koreanus Environ. Sci. Technol. 2019 53 7830 7839 31244070 10.1021/acs.est.9b01359 Lee, M. C. et al. Tributyltin affects retinoid X receptor-mediated lipid metabolism in the marine Rotifer Brachionus koreanus. Environ. Sci. Technol. 53 , 7830–7839 (2019). 31244070 10.1021/acs.est.9b01359

232. Xu Y O’Malley BW Elmquist JK Brain nuclear receptors and body weight regulation J. Clin. Invest. 2017 127 1172 1180 28218618 10.1172/JCI88891 PMC5373860 Xu, Y., O’Malley, B. W. & Elmquist, J. K. Brain nuclear receptors and body weight regulation. J. Clin. Invest. 127 , 1172–1180 (2017). 28218618 10.1172/JCI88891 PMC5373860

233. Ding L Yang L Wang Z Huang W Bile acid nuclear receptor FXR and digestive system diseases Acta Pharm. Sin. B 2015 5 135 144 26579439 10.1016/j.apsb.2015.01.004 PMC4629217 Ding, L., Yang, L., Wang, Z. & Huang, W. Bile acid nuclear receptor FXR and digestive system diseases. Acta Pharm. Sin. B 5 , 135–144 (2015). 26579439 10.1016/j.apsb.2015.01.004 PMC4629217

234. Nicolini A Ferrari P Duffy MJ Prognostic and predictive biomarkers in breast cancer: Past, present and future Semin. Cancer Biol. 2018 52 56 73 28882552 10.1016/j.semcancer.2017.08.010 Nicolini, A., Ferrari, P. & Duffy, M. J. Prognostic and predictive biomarkers in breast cancer: Past, present and future. Semin. Cancer Biol. 52 , 56–73 (2018). 28882552 10.1016/j.semcancer.2017.08.010

235. Xu Y ZNF397 deficiency triggers TET2-driven lineage plasticity and AR-targeted therapy resistance in prostate cancer Cancer Discov. 2024 14 1496 1521 38591846 10.1158/2159-8290.CD-23-0539 PMC11285331 Xu, Y. et al. ZNF397 deficiency triggers TET2-driven lineage plasticity and AR-targeted therapy resistance in prostate cancer. Cancer Discov. 14 , 1496–1521 (2024). 38591846 10.1158/2159-8290.CD-23-0539 PMC11285331

236. Alfarhan MW Al-Hussaini H Kilarkaje N Role of PPAR-γ in diabetes-induced testicular dysfunction, oxidative DNA damage and repair in leptin receptor-deficient obese type 2 diabetic mice Chem. Biol. Interact. 2022 361 109958 35472412 10.1016/j.cbi.2022.109958 Alfarhan, M. W., Al-Hussaini, H. & Kilarkaje, N. Role of PPAR-γ in diabetes-induced testicular dysfunction, oxidative DNA damage and repair in leptin receptor-deficient obese type 2 diabetic mice. Chem. Biol. Interact. 361 , 109958 (2022). 35472412 10.1016/j.cbi.2022.109958

237. Dragoljevic D Administration of an LXR agonist promotes atherosclerotic lesion remodelling in murine inflammatory arthritis Clin. Transl. Immunol. 2023 12 e1446 10.1002/cti2.1446 PMC10113696 37091327 Dragoljevic, D. et al. Administration of an LXR agonist promotes atherosclerotic lesion remodelling in murine inflammatory arthritis. Clin. Transl. Immunol. 12 , e1446 (2023). 10.1002/cti2.1446 PMC10113696 37091327

238. Kumar M Salem K Jeffery JJ Fowler AM PET imaging of estrogen receptors using (18)F-based radioligands Methods Mol. Biol. 2022 2418 129 151 35119664 10.1007/978-1-0716-1920-9_9 Kumar, M., Salem, K., Jeffery, J. J. & Fowler, A. M. PET imaging of estrogen receptors using (18)F-based radioligands. Methods Mol. Biol. 2418 , 129–151 (2022). 35119664 10.1007/978-1-0716-1920-9_9

239. Yang, J. et al. Mecp2 fine-tunes quiescence exit by targeting nuclear receptors. Elife . 12 , (2024). 10.7554/eLife.89912 PMC11095939 38747706

240. Zhao Y Nr5a2 ensures inner cell mass formation in mouse blastocyst Cell Rep. 2024 43 113840 38386558 10.1016/j.celrep.2024.113840 Zhao, Y. et al. Nr5a2 ensures inner cell mass formation in mouse blastocyst. Cell Rep. 43 , 113840 (2024). 38386558 10.1016/j.celrep.2024.113840

241. Wan R NR2F2 alleviates pulmonary fibrosis by inhibition of epithelial cell senescence Respir. Res. 2024 25 154 38566093 10.1186/s12931-024-02777-3 PMC10985909 Wan, R. et al. NR2F2 alleviates pulmonary fibrosis by inhibition of epithelial cell senescence. Respir. Res. 25 , 154 (2024). 38566093 10.1186/s12931-024-02777-3 PMC10985909

242. Wang C Z-ligustilide selectively targets AML by restoring nuclear receptors Nur77 and NOR-1-mediated apoptosis and differentiation Phytomedicine 2021 82 153448 33421904 10.1016/j.phymed.2020.153448 Wang, C. et al. Z-ligustilide selectively targets AML by restoring nuclear receptors Nur77 and NOR-1-mediated apoptosis and differentiation. Phytomedicine 82 , 153448 (2021). 33421904 10.1016/j.phymed.2020.153448

243. Clarisse D Offner F De Bosscher K Latest perspectives on glucocorticoid-induced apoptosis and resistance in lymphoid malignancies Biochim. Biophys. Acta 2020 1874 188430 10.1016/j.bbcan.2020.188430 32950642 Clarisse, D., Offner, F. & De Bosscher, K. Latest perspectives on glucocorticoid-induced apoptosis and resistance in lymphoid malignancies. Biochim. Biophys. Acta 1874 , 188430 (2020). 10.1016/j.bbcan.2020.188430 32950642

244. Arnesen S Estrogen receptor alpha mutations in breast cancer cells cause gene expression changes through constant activity and secondary effects Cancer Res. 2021 81 539 551 33184109 10.1158/0008-5472.CAN-20-1171 PMC7854489 Arnesen, S., et al. Estrogen receptor alpha mutations in breast cancer cells cause gene expression changes through constant activity and secondary effects. Cancer Res. 81 , 539–551 (2021). 33184109 10.1158/0008-5472.CAN-20-1171 PMC7854489

245. Pakdel, F. The role of estrogen receptors in health and disease. Int. J. Mol. Sci . 24 , (2023). 10.3390/ijms241411354 PMC10378944 37511113

246. Farcas, A. M., Nagarajan, S., Cosulich, S. & Carroll, J. S. Genome-wide estrogen receptor activity in breast cancer. Endocrinology . 162 , (2021). 10.1210/endocr/bqaa224 PMC7787425 33284960

247. Ross-Innes CS Differential oestrogen receptor binding is associated with clinical outcome in breast cancer Nature 2012 481 389 393 22217937 10.1038/nature10730 PMC3272464 Ross-Innes, C. S. et al. Differential oestrogen receptor binding is associated with clinical outcome in breast cancer. Nature 481 , 389–393 (2012). 22217937 10.1038/nature10730 PMC3272464

248. Chen H A pan-cancer analysis of enhancer expression in nearly 9000 patient samples Cell 2018 173 386 399.e312 29625054 10.1016/j.cell.2018.03.027 PMC5890960 Chen, H. et al. A pan-cancer analysis of enhancer expression in nearly 9000 patient samples. Cell 173 , 386–399.e312 (2018). 29625054 10.1016/j.cell.2018.03.027 PMC5890960

249. Maurya, S. S. Role of enhancers in development and diseases. Epigenomes . 5 , (2021). 10.3390/epigenomes5040021 PMC8715447 34968246

250. Rashid A Roscovitine enhances All-trans retinoic acid (ATRA)-induced leukemia cell differentiation: Novel effects on signaling molecules for a putative Cdk2 inhibitor Cell. Signal. 2020 71 109555 32032659 10.1016/j.cellsig.2020.109555 Rashid, A. et al. Roscovitine enhances All-trans retinoic acid (ATRA)-induced leukemia cell differentiation: Novel effects on signaling molecules for a putative Cdk2 inhibitor. Cell. Signal. 71 , 109555 (2020). 32032659 10.1016/j.cellsig.2020.109555

251. Rashid, A. et al. Roscovitine enhances all- trans retinoic acid (ATRA)-induced nuclear enrichment of an ensemble of activated signaling molecules and augments ATRA-induced myeloid cell differentiation. Oncotarget . 11 , (2020). 10.18632/oncotarget.27508 PMC7105165 32256976

252. Salehpour A 1,25-Dihydroxyvitamin D3 modulates adipogenesis of human adipose-derived mesenchymal stem cells dose-dependently Nutr. Metab. (Lond.). 2021 18 29 33712053 10.1186/s12986-021-00561-4 PMC7953614 Salehpour, A. et al. 1,25-Dihydroxyvitamin D3 modulates adipogenesis of human adipose-derived mesenchymal stem cells dose-dependently. Nutr. Metab. (Lond.). 18 , 29 (2021). 33712053 10.1186/s12986-021-00561-4 PMC7953614

253. Caccavale, F. et al. Crosstalk between nitric oxide and retinoic acid pathways is essential for amphioxus pharynx development. Elife . 10 , (2021). 10.7554/eLife.58295 PMC8387019 34431784

254. di Masi A Retinoic acid receptors: from molecular mechanisms to cancer therapy Mol. Asp. Med. 2015 41 1 115 10.1016/j.mam.2014.12.003 25543955 di Masi, A. et al. Retinoic acid receptors: from molecular mechanisms to cancer therapy. Mol. Asp. Med. 41 , 1–115 (2015). 10.1016/j.mam.2014.12.003 25543955

255. Yu G Retinoic acid receptor activation reduces metastatic prostate cancer bone lesions by blocking the endothelial-to-osteoblast transition Cancer Res 2022 82 3158 3171 35802768 10.1158/0008-5472.CAN-22-0170 PMC9444986 Yu, G. et al. Retinoic acid receptor activation reduces metastatic prostate cancer bone lesions by blocking the endothelial-to-osteoblast transition. Cancer Res 82 , 3158–3171 (2022). 35802768 10.1158/0008-5472.CAN-22-0170 PMC9444986

256. Yu G Multiple pathways coordinating reprogramming of endothelial cells into osteoblasts by BMP4 iScience 2021 24 102388 33981975 10.1016/j.isci.2021.102388 PMC8086028 Yu, G. et al. Multiple pathways coordinating reprogramming of endothelial cells into osteoblasts by BMP4. iScience 24 , 102388 (2021). 33981975 10.1016/j.isci.2021.102388 PMC8086028

257. Ke N Nuclear hormone receptor NR4A2 is involved in cell transformation and apoptosis Cancer Res 2004 64 8208 8212 15548686 10.1158/0008-5472.CAN-04-2134 Ke, N. et al. Nuclear hormone receptor NR4A2 is involved in cell transformation and apoptosis. Cancer Res 64 , 8208–8212 (2004). 15548686 10.1158/0008-5472.CAN-04-2134

258. Balasubramanian S Orphan nuclear receptor Nur77 promotes acute kidney injury and renal epithelial apoptosis J. Am. Soc. Nephrol. 2012 23 674 686 22343121 10.1681/ASN.2011070646 PMC3312507 Balasubramanian, S. et al. Orphan nuclear receptor Nur77 promotes acute kidney injury and renal epithelial apoptosis. J. Am. Soc. Nephrol. 23 , 674–686 (2012). 22343121 10.1681/ASN.2011070646 PMC3312507

259. He L A Regulation Loop Between YAP and NR4A1 balances cell proliferation and apoptosis Cell Rep. 2020 33 108284 33086070 10.1016/j.celrep.2020.108284 He, L. et al. A Regulation Loop Between YAP and NR4A1 balances cell proliferation and apoptosis. Cell Rep. 33 , 108284 (2020). 33086070 10.1016/j.celrep.2020.108284

260. Chen L Emodin promotes hepatic stellate cell senescence and alleviates liver fibrosis via a nuclear receptor (Nur77)-mediated epigenetic regulation of glutaminase 1 Br. J. Pharm. 2023 180 2577 2598 10.1111/bph.16156 37263753 Chen, L. et al. Emodin promotes hepatic stellate cell senescence and alleviates liver fibrosis via a nuclear receptor (Nur77)-mediated epigenetic regulation of glutaminase 1. Br. J. Pharm. 180 , 2577–2598 (2023). 10.1111/bph.16156 37263753

261. Wang Z Nuclear receptor HNF4α performs a tumor suppressor function in prostate cancer via its induction of p21-driven cellular senescence Oncogene 2020 39 1572 1589 31695151 10.1038/s41388-019-1080-3 PMC7018660 Wang, Z. et al. Nuclear receptor HNF4α performs a tumor suppressor function in prostate cancer via its induction of p21-driven cellular senescence. Oncogene 39 , 1572–1589 (2020). 31695151 10.1038/s41388-019-1080-3 PMC7018660

262. Xing Y Yan J Niu Y PXR: A center of transcriptional regulation in cancer Acta Pharm. Sin. B 2020 10 197 206 32082968 10.1016/j.apsb.2019.06.012 PMC7016272 Xing, Y., Yan, J. & Niu, Y. PXR: A center of transcriptional regulation in cancer. Acta Pharm. Sin. B 10 , 197–206 (2020). 32082968 10.1016/j.apsb.2019.06.012 PMC7016272

263. Ma X The nuclear receptor RXRA controls cellular senescence by regulating calcium signaling Aging Cell 2018 17 e12831 30216632 10.1111/acel.12831 PMC6260923 Ma, X. et al. The nuclear receptor RXRA controls cellular senescence by regulating calcium signaling. Aging Cell 17 , e12831 (2018). 30216632 10.1111/acel.12831 PMC6260923

264. Wang C Zinc finger protein ZBTB17 controls cellular senescence via interacting with nuclear receptor RXRA and its downstream calcium signaling FASEB J. 2023 37 e23193 37698375 10.1096/fj.202301050R Wang, C. et al. Zinc finger protein ZBTB17 controls cellular senescence via interacting with nuclear receptor RXRA and its downstream calcium signaling. FASEB J. 37 , e23193 (2023). 37698375 10.1096/fj.202301050R

265. Terao R LXR/CD38 activation drives cholesterol-induced macrophage senescence and neurodegeneration via NAD(+) depletion Cell Rep. 2024 43 114102 38636518 10.1016/j.celrep.2024.114102 PMC11223747 Terao, R. et al. LXR/CD38 activation drives cholesterol-induced macrophage senescence and neurodegeneration via NAD(+) depletion. Cell Rep. 43 , 114102 (2024). 38636518 10.1016/j.celrep.2024.114102 PMC11223747

266. Kumar, R. et al. Metabolic pathways, enzymes, and metabolites: Opportunities in cancer therapy. Cancers (Basel) . 14 , (2022). 10.3390/cancers14215268 PMC9656396 36358687

267. Marino JS Glucocorticoid Receptor β induces hepatic steatosis by augmenting inflammation and inhibition of the peroxisome proliferator-activated receptor (PPAR) α J. Biol. Chem. 2016 291 25776 25788 27784782 10.1074/jbc.M116.752311 PMC5203696 Marino, J. S. et al. Glucocorticoid Receptor β induces hepatic steatosis by augmenting inflammation and inhibition of the peroxisome proliferator-activated receptor (PPAR) α. J. Biol. Chem. 291 , 25776–25788 (2016). 27784782 10.1074/jbc.M116.752311 PMC5203696

268. Shimizu, M. & Sato, R. Endocrine fibroblast growth factors in relation to stress signaling. Cells . 11 , (2022). 10.3390/cells11030505 PMC8834311 35159314

269. Chatterjee N Perrimon N What fuels the fly: Energy metabolism in Drosophila and its application to the study of obesity and diabetes Sci. Adv. 2021 7 eabg4336 34108216 10.1126/sciadv.abg4336 PMC8189582 Chatterjee, N. & Perrimon, N. What fuels the fly: Energy metabolism in Drosophila and its application to the study of obesity and diabetes. Sci. Adv. 7 , eabg4336 (2021). 34108216 10.1126/sciadv.abg4336 PMC8189582

270. Gonzalez-Rellan MJ Fondevila MF Dieguez C Nogueiras R O-GlcNAcylation: A sweet hub in the regulation of glucose metabolism in health and disease Front. Endocrinol. (Lausanne) 2022 13 873513 35527999 10.3389/fendo.2022.873513 PMC9072661 Gonzalez-Rellan, M. J., Fondevila, M. F., Dieguez, C. & Nogueiras, R. O-GlcNAcylation: A sweet hub in the regulation of glucose metabolism in health and disease. Front. Endocrinol. (Lausanne) 13 , 873513 (2022). 35527999 10.3389/fendo.2022.873513 PMC9072661

271. Aronoff SL Berkowitz K Shreiner B Want L Glucose metabolism and regulation: Beyond insulin and glucagon Diab. Spectr. 2004 17 183 190 Aronoff, S. L., Berkowitz, K., Shreiner, B. & Want, L. Glucose metabolism and regulation: Beyond insulin and glucagon. Diab. Spectr. 17 , 183–190 (2004).

272. Hatano R Hepatic ketone body regulation of renal gluconeogenesis Mol. Metab. 2024 84 101934 38604598 10.1016/j.molmet.2024.101934 PMC11039402 Hatano, R. et al. Hepatic ketone body regulation of renal gluconeogenesis. Mol. Metab. 84 , 101934 (2024). 38604598 10.1016/j.molmet.2024.101934 PMC11039402

273. Zhao Y Histone phosphorylation integrates the hepatic glucagon-PKA-CREB gluconeogenesis program in response to fasting Mol. Cell 2023 83 1093 1108.e1098 36863348 10.1016/j.molcel.2023.02.007 Zhao, Y. et al. Histone phosphorylation integrates the hepatic glucagon-PKA-CREB gluconeogenesis program in response to fasting. Mol. Cell 83 , 1093–1108.e1098 (2023). 36863348 10.1016/j.molcel.2023.02.007

274. Yook JS The SLC25A47 locus controls gluconeogenesis and energy expenditure Proc. Natl. Acad. Sci. USA 2023 120 e2216810120 36812201 10.1073/pnas.2216810120 PMC9992842 Yook, J. S. et al. The SLC25A47 locus controls gluconeogenesis and energy expenditure. Proc. Natl. Acad. Sci. USA 120 , e2216810120 (2023). 36812201 10.1073/pnas.2216810120 PMC9992842

275. Hassan, F. U. et al. Role of peroxisome proliferator-activated receptors (PPARs) in energy homeostasis of dairy animals: ExplOiting Their Modulation Through Nutrigenomic Interventions. Int. J. Mol. Sci . 22 , (2021). 10.3390/ijms222212463 PMC8619600 34830341

276. Ramatchandirin, B., Pearah, A. & He, L. Regulation of liver glucose and lipid metabolism by transcriptional factors and coactivators. Life (Basel) . 13 , (2023). 10.3390/life13020515 PMC9962321 36836874

277. Hassani-Nezhad-Gashti F Activation of nuclear receptor PXR impairs glucose tolerance and dysregulates GLUT2 expression and subcellular localization in liver Biochem Pharm. 2018 148 253 264 29309761 10.1016/j.bcp.2018.01.001 Hassani-Nezhad-Gashti, F. et al. Activation of nuclear receptor PXR impairs glucose tolerance and dysregulates GLUT2 expression and subcellular localization in liver. Biochem Pharm. 148 , 253–264 (2018). 29309761 10.1016/j.bcp.2018.01.001

278. Mitro N The nuclear receptor LXR is a glucose sensor Nature 2007 445 219 223 17187055 10.1038/nature05449 Mitro, N. et al. The nuclear receptor LXR is a glucose sensor. Nature 445 , 219–223 (2007). 17187055 10.1038/nature05449

279. Miao L Glycerol kinase interacts with nuclear receptor NR4A1 and regulates glucose metabolism in the liver FASEB J. 2019 33 6736 6747 30821173 10.1096/fj.201800945RR Miao, L. et al. Glycerol kinase interacts with nuclear receptor NR4A1 and regulates glucose metabolism in the liver. FASEB J. 33 , 6736–6747 (2019). 30821173 10.1096/fj.201800945RR

280. Martin Vázquez E NR5A2/LRH-1 regulates the PTGS2-PGE(2)-PTGER1 pathway contributing to pancreatic islet survival and function iScience 2022 25 104345 35602948 10.1016/j.isci.2022.104345 PMC9117883 Martin Vázquez, E. et al. NR5A2/LRH-1 regulates the PTGS2-PGE(2)-PTGER1 pathway contributing to pancreatic islet survival and function. iScience 25 , 104345 (2022). 35602948 10.1016/j.isci.2022.104345 PMC9117883

281. Sun Y Demagny H Schoonjans K Emerging functions of the nuclear receptor LRH-1 in liver physiology and pathology Biochim Biophys. Acta Mol. Basis Dis. 2021 1867 166145 33862147 10.1016/j.bbadis.2021.166145 Sun, Y., Demagny, H. & Schoonjans, K. Emerging functions of the nuclear receptor LRH-1 in liver physiology and pathology. Biochim Biophys. Acta Mol. Basis Dis. 1867 , 166145 (2021). 33862147 10.1016/j.bbadis.2021.166145

282. Ploton M The nuclear bile acid receptor FXR is a PKA- and FOXA2-sensitive activator of fasting hepatic gluconeogenesis J. Hepatol. 2018 69 1099 1109 29981427 10.1016/j.jhep.2018.06.022 Ploton, M. et al. The nuclear bile acid receptor FXR is a PKA- and FOXA2-sensitive activator of fasting hepatic gluconeogenesis. J. Hepatol. 69 , 1099–1109 (2018). 29981427 10.1016/j.jhep.2018.06.022

283. Hauck AK Nuclear receptor corepressors non-canonically drive glucocorticoid receptor-dependent activation of hepatic gluconeogenesis Nat. Metab. 2024 6 825 836 38622413 10.1038/s42255-024-01029-4 PMC11459266 Hauck, A. K. et al. Nuclear receptor corepressors non-canonically drive glucocorticoid receptor-dependent activation of hepatic gluconeogenesis. Nat. Metab. 6 , 825–836 (2024). 38622413 10.1038/s42255-024-01029-4 PMC11459266

284. Xie Y Deficiency of nuclear receptor coactivator 3 aggravates diabetic kidney disease by impairing podocyte autophagy Adv. Sci. (Weinh.) 2024 11 e2308378 38483947 10.1002/advs.202308378 PMC11109634 Xie, Y. et al. Deficiency of nuclear receptor coactivator 3 aggravates diabetic kidney disease by impairing podocyte autophagy. Adv. Sci. (Weinh.) 11 , e2308378 (2024). 38483947 10.1002/advs.202308378 PMC11109634

285. Wang F Essential role of nuclear receptors for the evaluation of the benefits of bioactive herbal extracts on liver function Biomed. Pharmacother. 2018 99 798 809 29710478 10.1016/j.biopha.2018.01.012 Wang, F. et al. Essential role of nuclear receptors for the evaluation of the benefits of bioactive herbal extracts on liver function. Biomed. Pharmacother. 99 , 798–809 (2018). 29710478 10.1016/j.biopha.2018.01.012

286. Chiang JYL Ferrell JM Discovery of farnesoid X receptor and its role in bile acid metabolism Mol. Cell Endocrinol. 2022 548 111618 35283218 10.1016/j.mce.2022.111618 PMC9038687 Chiang, J. Y. L. & Ferrell, J. M. Discovery of farnesoid X receptor and its role in bile acid metabolism. Mol. Cell Endocrinol. 548 , 111618 (2022). 35283218 10.1016/j.mce.2022.111618 PMC9038687

287. Bougarne N Molecular actions of PPARα in lipid metabolism and inflammation Endocr. Rev. 2018 39 760 802 30020428 10.1210/er.2018-00064 Bougarne, N. et al. Molecular actions of PPARα in lipid metabolism and inflammation. Endocr. Rev. 39 , 760–802 (2018). 30020428 10.1210/er.2018-00064

288. Lamichane, S., Dahal Lamichane, B. & Kwon, S. M. Pivotal roles of peroxisome proliferator-activated receptors (PPARs) and their signal cascade for cellular and whole-body energy homeostasis. Int. J. Mol. Sci . 19 , (2018). 10.3390/ijms19040949 PMC5979443 29565812

289. Guajardo-Correa, E. et al. Estrogen signaling as a bridge between the nucleus and mitochondria in cardiovascular diseases. Front. Cell Dev. Biol . 10 , (2022). 10.3389/fcell.2022.968373 PMC9516331 36187489

290. Chen CY Inhibition of estrogen-related receptor α blocks liver steatosis and steatohepatitis and attenuates triglyceride biosynthesis Am. J. Pathol. 2021 191 1240 1254 33894178 10.1016/j.ajpath.2021.04.007 PMC8261472 Chen, C. Y. et al. Inhibition of estrogen-related receptor α blocks liver steatosis and steatohepatitis and attenuates triglyceride biosynthesis. Am. J. Pathol. 191 , 1240–1254 (2021). 33894178 10.1016/j.ajpath.2021.04.007 PMC8261472

291. Gulick T The peroxisome proliferator-activated receptor regulates mitochondrial fatty acid oxidative enzyme gene expression Proc. Natl. Acad. Sci. USA 1994 91 11012 11016 7971999 10.1073/pnas.91.23.11012 PMC45156 Gulick, T. et al. The peroxisome proliferator-activated receptor regulates mitochondrial fatty acid oxidative enzyme gene expression. Proc. Natl. Acad. Sci. USA 91 , 11012–11016 (1994). 7971999 10.1073/pnas.91.23.11012 PMC45156

292. Huang CY PERM1 regulates genes involved in fatty acid metabolism in the heart by interacting with PPARα and PGC-1α Sci. Rep. 2022 12 14576 36028747 10.1038/s41598-022-18885-3 PMC9418182 Huang, C. Y. et al. PERM1 regulates genes involved in fatty acid metabolism in the heart by interacting with PPARα and PGC-1α. Sci. Rep. 12 , 14576 (2022). 36028747 10.1038/s41598-022-18885-3 PMC9418182

293. Montagner A Liver PPARα is crucial for whole-body fatty acid homeostasis and is protective against NAFLD Gut 2016 65 1202 1214 26838599 10.1136/gutjnl-2015-310798 PMC4941147 Montagner, A. et al. Liver PPARα is crucial for whole-body fatty acid homeostasis and is protective against NAFLD. Gut 65 , 1202–1214 (2016). 26838599 10.1136/gutjnl-2015-310798 PMC4941147

294. Iershov A The class 3 PI3K coordinates autophagy and mitochondrial lipid catabolism by controlling nuclear receptor PPARα Nat. Commun. 2019 10 1566 30952952 10.1038/s41467-019-09598-9 PMC6451001 Iershov, A. et al. The class 3 PI3K coordinates autophagy and mitochondrial lipid catabolism by controlling nuclear receptor PPARα. Nat. Commun. 10 , 1566 (2019). 30952952 10.1038/s41467-019-09598-9 PMC6451001

295. Geiger M Genetic deletion of hepatic NCOR1 protects from atherosclerosis by promoting alternative bile acid-metabolism and sterol excretion Cardiovasc. Diabetol. 2023 22 144 37349757 10.1186/s12933-023-01865-w PMC10288794 Geiger, M. et al. Genetic deletion of hepatic NCOR1 protects from atherosclerosis by promoting alternative bile acid-metabolism and sterol excretion. Cardiovasc. Diabetol. 22 , 144 (2023). 37349757 10.1186/s12933-023-01865-w PMC10288794

296. Zhang Y Targeting nuclear receptor NR4A1-dependent adipocyte progenitor quiescence promotes metabolic adaptation to obesity J. Clin. Invest. 2018 128 4898 4911 30277475 10.1172/JCI98353 PMC6205397 Zhang, Y. et al. Targeting nuclear receptor NR4A1-dependent adipocyte progenitor quiescence promotes metabolic adaptation to obesity. J. Clin. Invest. 128 , 4898–4911 (2018). 30277475 10.1172/JCI98353 PMC6205397

297. Qin DD NR4A1 retards adipocyte differentiation or maturation via enhancing GATA2 and p53 expression J. Cell. Mol. Med. 2018 22 4709 4720 30044048 10.1111/jcmm.13715 PMC6156289 Qin, D. D. et al. NR4A1 retards adipocyte differentiation or maturation via enhancing GATA2 and p53 expression. J. Cell. Mol. Med. 22 , 4709–4720 (2018). 30044048 10.1111/jcmm.13715 PMC6156289

298. Kim YC Small heterodimer partner and fibroblast growth factor 19 inhibit expression of NPC1L1 in mouse intestine and cholesterol absorption Gastroenterology 2019 156 1052 1065 30521806 10.1053/j.gastro.2018.11.061 PMC6409196 Kim, Y. C. et al. Small heterodimer partner and fibroblast growth factor 19 inhibit expression of NPC1L1 in mouse intestine and cholesterol absorption. Gastroenterology 156 , 1052–1065 (2019). 30521806 10.1053/j.gastro.2018.11.061 PMC6409196

299. Ito K Critical roles of transcriptional coactivator MED1 in the formation and function of mouse adipose tissues Genes Dev. 2021 35 729 748 33888560 10.1101/gad.346791.120 PMC8091968 Ito, K. et al. Critical roles of transcriptional coactivator MED1 in the formation and function of mouse adipose tissues. Genes Dev. 35 , 729–748 (2021). 33888560 10.1101/gad.346791.120 PMC8091968

300. Zhou J MED1 mediator subunit is a key regulator of hepatic autophagy and lipid metabolism Autophagy 2021 17 4043 4061 33734012 10.1080/15548627.2021.1899691 PMC8726716 Zhou, J. et al. MED1 mediator subunit is a key regulator of hepatic autophagy and lipid metabolism. Autophagy 17 , 4043–4061 (2021). 33734012 10.1080/15548627.2021.1899691 PMC8726716

301. Cai C Cai P Chu G Selection of suitable reference genes for core clock gene expression analysis by real-time qPCR in rat ovary granulosa cells Mol. Biol. Rep. 2019 46 2941 2946 31016616 10.1007/s11033-019-04755-1 Cai, C., Cai, P. & Chu, G. Selection of suitable reference genes for core clock gene expression analysis by real-time qPCR in rat ovary granulosa cells. Mol. Biol. Rep. 46 , 2941–2946 (2019). 31016616 10.1007/s11033-019-04755-1

302. Zhu K An intrinsically disordered region controlling condensation of a circadian clock component and rhythmic transcription in the liver Mol. Cell 2023 83 3457 3469.e3457 37802023 10.1016/j.molcel.2023.09.010 PMC10575687 Zhu, K. et al. An intrinsically disordered region controlling condensation of a circadian clock component and rhythmic transcription in the liver. Mol. Cell 83 , 3457–3469.e3457 (2023). 37802023 10.1016/j.molcel.2023.09.010 PMC10575687

303. Schibler U How the circadian nuclear orphan receptor REV-ERBα represses transcription: Temporal and spatial phase separation combined Mol. Cell 2023 83 3399 3401 37802021 10.1016/j.molcel.2023.09.017 Schibler, U. How the circadian nuclear orphan receptor REV-ERBα represses transcription: Temporal and spatial phase separation combined. Mol. Cell 83 , 3399–3401 (2023). 37802021 10.1016/j.molcel.2023.09.017

304. Zhao X Nuclear receptors rock around the clock EMBO Rep. 2014 15 518 528 24737872 10.1002/embr.201338271 PMC4210094 Zhao, X. et al. Nuclear receptors rock around the clock. EMBO Rep. 15 , 518–528 (2014). 24737872 10.1002/embr.201338271 PMC4210094

305. Cai D RORγ is a targetable master regulator of cholesterol biosynthesis in a cancer subtype Nat. Commun. 2019 10 4621 31604910 10.1038/s41467-019-12529-3 PMC6789042 Cai, D. et al. RORγ is a targetable master regulator of cholesterol biosynthesis in a cancer subtype. Nat. Commun. 10 , 4621 (2019). 31604910 10.1038/s41467-019-12529-3 PMC6789042

306. Yu, X. et al. Nuclear receptor PXR targets AKR1B7 to protect mitochondrial metabolism and renal function in AKI. Sci. Transl. Med . 12 , (2020). 10.1126/scitranslmed.aay7591 32404507

307. Byun S Phosphorylation of hepatic farnesoid X receptor by FGF19 signaling-activated Src maintains cholesterol levels and protects from atherosclerosis J. Biol. Chem. 2019 294 8732 8744 30996006 10.1074/jbc.RA119.008360 PMC6552419 Byun, S. et al. Phosphorylation of hepatic farnesoid X receptor by FGF19 signaling-activated Src maintains cholesterol levels and protects from atherosclerosis. J. Biol. Chem. 294 , 8732–8744 (2019). 30996006 10.1074/jbc.RA119.008360 PMC6552419

308. Karpale M Activation of pregnane X receptor induces atherogenic lipids and PCSK9 by a SREBP2-mediated mechanism Br. J. Pharm. 2021 178 2461 2481 10.1111/bph.15433 33687065 Karpale, M. et al. Activation of pregnane X receptor induces atherogenic lipids and PCSK9 by a SREBP2-mediated mechanism. Br. J. Pharm. 178 , 2461–2481 (2021). 10.1111/bph.15433 33687065

309. Jin P Mitochondrial adaptation in cancer drug resistance: prevalence, mechanisms, and management J. Hematol. Oncol. 2022 15 97 35851420 10.1186/s13045-022-01313-4 PMC9290242 Jin, P. et al. Mitochondrial adaptation in cancer drug resistance: prevalence, mechanisms, and management. J. Hematol. Oncol. 15 , 97 (2022). 35851420 10.1186/s13045-022-01313-4 PMC9290242

310. Scholtes C Identification of a chromatin-bound ERRα interactome network in mouse liver Mol. Metab. 2024 83 101925 38537884 10.1016/j.molmet.2024.101925 PMC10990974 Scholtes, C. et al. Identification of a chromatin-bound ERRα interactome network in mouse liver. Mol. Metab. 83 , 101925 (2024). 38537884 10.1016/j.molmet.2024.101925 PMC10990974

311. Wu Z HDAC1 disrupts the tricarboxylic acid (TCA) cycle through the deacetylation of Nur77 and promotes inflammation in ischemia-reperfusion mice Cell Death Discov. 2023 9 10 36653355 10.1038/s41420-023-01308-1 PMC9849262 Wu, Z. et al. HDAC1 disrupts the tricarboxylic acid (TCA) cycle through the deacetylation of Nur77 and promotes inflammation in ischemia-reperfusion mice. Cell Death Discov. 9 , 10 (2023). 36653355 10.1038/s41420-023-01308-1 PMC9849262

312. Sacco SA Overexpression of peroxisome proliferator-activated receptor γ co-activator-1α (PGC-1α) in Chinese hamster ovary cells increases oxidative metabolism and IgG productivity Metab. Eng. 2023 79 108 117 37473833 10.1016/j.ymben.2023.07.005 Sacco, S. A. et al. Overexpression of peroxisome proliferator-activated receptor γ co-activator-1α (PGC-1α) in Chinese hamster ovary cells increases oxidative metabolism and IgG productivity. Metab. Eng. 79 , 108–117 (2023). 37473833 10.1016/j.ymben.2023.07.005

313. Kida YS ERRs mediate a metabolic switch required for somatic cell reprogramming to pluripotency Cell Stem Cell 2015 16 547 555 25865501 10.1016/j.stem.2015.03.001 PMC4427539 Kida, Y. S. et al. ERRs mediate a metabolic switch required for somatic cell reprogramming to pluripotency. Cell Stem Cell 16 , 547–555 (2015). 25865501 10.1016/j.stem.2015.03.001 PMC4427539

314. Singh, B. K. et al. Thyroid hormone receptor and ERRα coordinately regulate mitochondrial fission, mitophagy, biogenesis, and function. Sci Signal . 11 , (2018). 10.1126/scisignal.aam5855 29945885

315. Wattez JS Loss of skeletal muscle estrogen-related receptors leads to severe exercise intolerance Mol. Metab. 2023 68 101670 36642217 10.1016/j.molmet.2023.101670 PMC9938320 Wattez, J. S. et al. Loss of skeletal muscle estrogen-related receptors leads to severe exercise intolerance. Mol. Metab. 68 , 101670 (2023). 36642217 10.1016/j.molmet.2023.101670 PMC9938320

316. Sopariwala DH Innately expressed estrogen-related receptors in the skeletal muscle are indispensable for exercise fitness FASEB J. 2023 37 e22727 36583689 10.1096/fj.202201518R PMC10253228 Sopariwala, D. H. et al. Innately expressed estrogen-related receptors in the skeletal muscle are indispensable for exercise fitness. FASEB J. 37 , e22727 (2023). 36583689 10.1096/fj.202201518R PMC10253228

317. Gantner ML Complementary roles of estrogen-related receptors in brown adipocyte thermogenic function Endocrinology 2016 157 4770 4781 27763777 10.1210/en.2016-1767 PMC5133354 Gantner, M. L. et al. Complementary roles of estrogen-related receptors in brown adipocyte thermogenic function. Endocrinology 157 , 4770–4781 (2016). 27763777 10.1210/en.2016-1767 PMC5133354

318. Li XX Nuclear receptor Nur77 facilitates melanoma cell survival under metabolic stress by protecting fatty acid oxidation Mol. Cell 2018 69 480 492.e487 29395065 10.1016/j.molcel.2018.01.001 Li, X. X. et al. Nuclear receptor Nur77 facilitates melanoma cell survival under metabolic stress by protecting fatty acid oxidation. Mol. Cell 69 , 480–492.e487 (2018). 29395065 10.1016/j.molcel.2018.01.001

319. Peng SZ Phase separation of Nur77 mediates celastrol-induced mitophagy by promoting the liquidity of p62/SQSTM1 condensates Nat. Commun. 2021 12 5989 34645818 10.1038/s41467-021-26295-8 PMC8514450 Peng, S. Z. et al. Phase separation of Nur77 mediates celastrol-induced mitophagy by promoting the liquidity of p62/SQSTM1 condensates. Nat. Commun. 12 , 5989 (2021). 34645818 10.1038/s41467-021-26295-8 PMC8514450

320. Yin S Nur77 increases mitophagy and decreases aggregation of α-synuclein by modulating the p-c-Abl/p-PHB2 Y121 in α-synuclein PFF SH-SY5Y cells and mice Eur. J. Med. Chem. 2024 268 116251 38422699 10.1016/j.ejmech.2024.116251 Yin, S. et al. Nur77 increases mitophagy and decreases aggregation of α-synuclein by modulating the p-c-Abl/p-PHB2 Y121 in α-synuclein PFF SH-SY5Y cells and mice. Eur. J. Med. Chem. 268 , 116251 (2024). 38422699 10.1016/j.ejmech.2024.116251

321. Sun LY Nuclear receptor NR1D1 regulates abdominal aortic aneurysm development by targeting the mitochondrial tricarboxylic acid cycle enzyme aconitase-2 Circulation 2022 146 1591 1609 35880522 10.1161/CIRCULATIONAHA.121.057623 PMC9674448 Sun, L. Y. et al. Nuclear receptor NR1D1 regulates abdominal aortic aneurysm development by targeting the mitochondrial tricarboxylic acid cycle enzyme aconitase-2. Circulation 146 , 1591–1609 (2022). 35880522 10.1161/CIRCULATIONAHA.121.057623 PMC9674448

322. Ling Z-N Amino acid metabolism in health and disease Signal Transduct. Target. Ther. 2023 8 345 37699892 10.1038/s41392-023-01569-3 PMC10497558 Ling, Z.-N. et al. Amino acid metabolism in health and disease. Signal Transduct. Target. Ther. 8 , 345 (2023). 37699892 10.1038/s41392-023-01569-3 PMC10497558

323. Torres, N. et al. Amino acid catabolism: An overlooked area of metabolism. Nutrients . 15 , (2023). 10.3390/nu15153378 PMC10421169 37571315

324. Dhillon P The nuclear receptor ESRRA protects from kidney disease by coupling metabolism and differentiation Cell Metab. 2021 33 379 394.e378 33301705 10.1016/j.cmet.2020.11.011 PMC9259369 Dhillon, P. et al. The nuclear receptor ESRRA protects from kidney disease by coupling metabolism and differentiation. Cell Metab. 33 , 379–394.e378 (2021). 33301705 10.1016/j.cmet.2020.11.011 PMC9259369

325. Sjögren RJO Branched-chain amino acid metabolism is regulated by ERRα in primary human myotubes and is further impaired by glucose loading in type 2 diabetes Diabetologia 2021 64 2077 2091 34131782 10.1007/s00125-021-05481-9 PMC8382616 Sjögren, R. J. O. et al. Branched-chain amino acid metabolism is regulated by ERRα in primary human myotubes and is further impaired by glucose loading in type 2 diabetes. Diabetologia 64 , 2077–2091 (2021). 34131782 10.1007/s00125-021-05481-9 PMC8382616

326. Tobón-Cornejo S PPARα/RXRα downregulates amino acid catabolism in the liver via interaction with HNF4α promoting its proteasomal degradation Metabolism 2021 116 154705 33422545 10.1016/j.metabol.2021.154705 Tobón-Cornejo, S. et al. PPARα/RXRα downregulates amino acid catabolism in the liver via interaction with HNF4α promoting its proteasomal degradation. Metabolism 116 , 154705 (2021). 33422545 10.1016/j.metabol.2021.154705

327. Shiozaki Y Miyazaki-Anzai S Keenan AL Miyazaki M MEF2D-NR4A1-FAM134B2-mediated reticulophagy contributes to amino acid homeostasis Autophagy 2022 18 1049 1061 34517786 10.1080/15548627.2021.1968228 PMC9196825 Shiozaki, Y., Miyazaki-Anzai, S., Keenan, A. L. & Miyazaki, M. MEF2D-NR4A1-FAM134B2-mediated reticulophagy contributes to amino acid homeostasis. Autophagy 18 , 1049–1061 (2022). 34517786 10.1080/15548627.2021.1968228 PMC9196825

328. Koenis DS Nuclear receptor Nur77 limits the macrophage inflammatory response through transcriptional reprogramming of mitochondrial metabolism Cell Rep. 2018 24 2127 2140.e2127 30134173 10.1016/j.celrep.2018.07.065 PMC6113932 Koenis, D. S. et al. Nuclear receptor Nur77 limits the macrophage inflammatory response through transcriptional reprogramming of mitochondrial metabolism. Cell Rep. 24 , 2127–2140.e2127 (2018). 30134173 10.1016/j.celrep.2018.07.065 PMC6113932

329. Han YH RORα induces KLF4-mediated M2 polarization in the liver macrophages that protect against nonalcoholic steatohepatitis Cell Rep. 2017 20 124 135 28683306 10.1016/j.celrep.2017.06.017 Han, Y. H. et al. RORα induces KLF4-mediated M2 polarization in the liver macrophages that protect against nonalcoholic steatohepatitis. Cell Rep. 20 , 124–135 (2017). 28683306 10.1016/j.celrep.2017.06.017

330. Zhou, J. et al. Orphan nuclear receptor TLX promotes immunosuppression via its transcriptional activation of PD-L1 in glioma. J. Immunother. Cancer . 9 , (2021). 10.1136/jitc-2020-001937 PMC8055120 33858847

331. Liu H NR1D1 modulates synovial inflammation and bone destruction in rheumatoid arthritis Cell Death Dis. 2020 11 129 32071294 10.1038/s41419-020-2314-6 PMC7028921 Liu, H. et al. NR1D1 modulates synovial inflammation and bone destruction in rheumatoid arthritis. Cell Death Dis. 11 , 129 (2020). 32071294 10.1038/s41419-020-2314-6 PMC7028921

332. Liu X Genome-wide analysis identifies NR4A1 as a key mediator of T cell dysfunction Nature 2019 567 525 529 30814730 10.1038/s41586-019-0979-8 PMC6507425 Liu, X. et al. Genome-wide analysis identifies NR4A1 as a key mediator of T cell dysfunction. Nature 567 , 525–529 (2019). 30814730 10.1038/s41586-019-0979-8 PMC6507425

333. Chen J NR4A transcription factors limit CAR T cell function in solid tumours Nature 2019 567 530 534 30814732 10.1038/s41586-019-0985-x PMC6546093 Chen, J. et al. NR4A transcription factors limit CAR T cell function in solid tumours. Nature 567 , 530–534 (2019). 30814732 10.1038/s41586-019-0985-x PMC6546093

334. Ghyselinck, N. B. & Duester, G. Retinoic acid signaling pathways. Development . 146 , (2019). 10.1242/dev.167502 PMC6633611 31273085

335. Larange A A regulatory circuit controlled by extranuclear and nuclear retinoic acid receptor α determines T cell activation and function Immunity 2023 56 2054 2069.e2010 37597518 10.1016/j.immuni.2023.07.017 PMC10552917 Larange, A. et al. A regulatory circuit controlled by extranuclear and nuclear retinoic acid receptor α determines T cell activation and function. Immunity 56 , 2054–2069.e2010 (2023). 37597518 10.1016/j.immuni.2023.07.017 PMC10552917

336. Sarubin N The sex-dependent role of the glucocorticoid receptor in depression: variations in the NR3C1 gene are associated with major depressive disorder in women but not in men Eur. Arch. Psychiatry Clin. Neurosci. 2017 267 123 133 27549215 10.1007/s00406-016-0722-5 Sarubin, N. et al. The sex-dependent role of the glucocorticoid receptor in depression: variations in the NR3C1 gene are associated with major depressive disorder in women but not in men. Eur. Arch. Psychiatry Clin. Neurosci. 267 , 123–133 (2017). 27549215 10.1007/s00406-016-0722-5

337. Mark M Ghyselinck NB Chambon P Function of retinoic acid receptors during embryonic development Nucl. Recept Signal 2009 7 e002 19381305 10.1621/nrs.07002 PMC2670431 Mark, M., Ghyselinck, N. B. & Chambon, P. Function of retinoic acid receptors during embryonic development. Nucl. Recept Signal 7 , e002 (2009). 19381305 10.1621/nrs.07002 PMC2670431

338. Chen J Progressive reduction of nuclear receptor Nr4a1 mediates age-dependent cognitive decline Alzheimers Dement 2024 20 3504 3524 38605605 10.1002/alz.13819 PMC11095431 Chen, J. et al. Progressive reduction of nuclear receptor Nr4a1 mediates age-dependent cognitive decline. Alzheimers Dement 20 , 3504–3524 (2024). 38605605 10.1002/alz.13819 PMC11095431

339. Ekimoto T Kudo T Yamane T Ikeguchi M Mechanism of vitamin D receptor ligand-binding domain regulation studied by gREST simulations J. Chem. Inf. Model. 2021 61 3625 3637 34189910 10.1021/acs.jcim.1c00534 Ekimoto, T., Kudo, T., Yamane, T. & Ikeguchi, M. Mechanism of vitamin D receptor ligand-binding domain regulation studied by gREST simulations. J. Chem. Inf. Model. 61 , 3625–3637 (2021). 34189910 10.1021/acs.jcim.1c00534

340. Wang N Ligand binding and heterodimerization with retinoid X receptor α (RXRα) induce farnesoid X receptor (FXR) conformational changes affecting coactivator binding J. Biol. Chem. 2018 293 18180 18191 30275017 10.1074/jbc.RA118.004652 PMC6254343 Wang, N. et al. Ligand binding and heterodimerization with retinoid X receptor α (RXRα) induce farnesoid X receptor (FXR) conformational changes affecting coactivator binding. J. Biol. Chem. 293 , 18180–18191 (2018). 30275017 10.1074/jbc.RA118.004652 PMC6254343

341. Hashiguchi T Phosphorylation of farnesoid X receptor at serine 154 links ligand activation with degradation Mol. Endocrinol. 2016 30 1070 1080 27571290 10.1210/me.2016-1105 PMC5045495 Hashiguchi, T. et al. Phosphorylation of farnesoid X receptor at serine 154 links ligand activation with degradation. Mol. Endocrinol. 30 , 1070–1080 (2016). 27571290 10.1210/me.2016-1105 PMC5045495

342. Stein S Impaired SUMOylation of nuclear receptor LRH-1 promotes nonalcoholic fatty liver disease J. Clin. Invest. 2017 127 583 592 28094767 10.1172/JCI85499 PMC5272172 Stein, S. et al. Impaired SUMOylation of nuclear receptor LRH-1 promotes nonalcoholic fatty liver disease. J. Clin. Invest. 127 , 583–592 (2017). 28094767 10.1172/JCI85499 PMC5272172

343. He Y PPARγ acetylation orchestrates adipose plasticity and metabolic rhythms Adv. Sci. (Weinh.) 2023 10 e2204190 36394167 10.1002/advs.202204190 PMC9839851 He, Y. et al. PPARγ acetylation orchestrates adipose plasticity and metabolic rhythms. Adv. Sci. (Weinh.) 10 , e2204190 (2023). 36394167 10.1002/advs.202204190 PMC9839851

344. Ikegami K Refetoff S Van Cauter E Yoshimura T Interconnection between circadian clocks and thyroid function Nat. Rev. Endocrinol. 2019 15 590 600 31406343 10.1038/s41574-019-0237-z PMC7288350 Ikegami, K., Refetoff, S., Van Cauter, E. & Yoshimura, T. Interconnection between circadian clocks and thyroid function. Nat. Rev. Endocrinol. 15 , 590–600 (2019). 31406343 10.1038/s41574-019-0237-z PMC7288350

345. Kim YH Lazar MA TranscRiptional Control Of Circadian Rhythms And Metabolism: A matter of time and space Endocr. Rev. 2020 41 bnaa014 32392281 10.1210/endrev/bnaa014 PMC7334005 Kim, Y. H. & Lazar, M. A. TranscRiptional Control Of Circadian Rhythms And Metabolism: A matter of time and space. Endocr. Rev. 41 , bnaa014 (2020). 32392281 10.1210/endrev/bnaa014 PMC7334005

346. Guo J Aging and aging-related diseases: From molecular mechanisms to interventions and treatments Signal Transduct. Target. Ther. 2022 7 391 36522308 10.1038/s41392-022-01251-0 PMC9755275 Guo, J. et al. Aging and aging-related diseases: From molecular mechanisms to interventions and treatments. Signal Transduct. Target. Ther. 7 , 391 (2022). 36522308 10.1038/s41392-022-01251-0 PMC9755275

347. Frankowska N Lisowska K Witkowski JM Proteolysis dysfunction in the process of aging and age-related diseases Front Aging 2022 3 927630 35958270 10.3389/fragi.2022.927630 PMC9361021 Frankowska, N., Lisowska, K. & Witkowski, J. M. Proteolysis dysfunction in the process of aging and age-related diseases. Front Aging 3 , 927630 (2022). 35958270 10.3389/fragi.2022.927630 PMC9361021

348. Reich N Hölscher C The neuroprotective effects of glucagon-like peptide 1 in Alzheimer’s and Parkinson’s disease: An in-depth review Front. Neurosci. 2022 16 970925 36117625 10.3389/fnins.2022.970925 PMC9475012 Reich, N. & Hölscher, C. The neuroprotective effects of glucagon-like peptide 1 in Alzheimer’s and Parkinson’s disease: An in-depth review. Front. Neurosci. 16 , 970925 (2022). 36117625 10.3389/fnins.2022.970925 PMC9475012

349. Brown MR The nuclear receptor REV-ERBα is implicated in the alteration of β-cell autophagy and survival under diabetogenic conditions Cell Death Dis. 2022 13 353 35428762 10.1038/s41419-022-04767-z PMC9012816 Brown, M. R. et al. The nuclear receptor REV-ERBα is implicated in the alteration of β-cell autophagy and survival under diabetogenic conditions. Cell Death Dis. 13 , 353 (2022). 35428762 10.1038/s41419-022-04767-z PMC9012816

350. Li P Autophagy and aging: Roles in skeletal muscle, eye, brain and hepatic tissue Front Cell Dev. Biol. 2021 9 752962 34778264 10.3389/fcell.2021.752962 PMC8581214 Li, P. et al. Autophagy and aging: Roles in skeletal muscle, eye, brain and hepatic tissue. Front Cell Dev. Biol. 9 , 752962 (2021). 34778264 10.3389/fcell.2021.752962 PMC8581214

351. Doering KRS Ermakova G Taubert S Nuclear hormone receptor NHR-49 is an essential regulator of stress resilience and healthy aging in Caenorhabditis elegans Front. Physiol. 2023 14 1241591 37645565 10.3389/fphys.2023.1241591 PMC10461480 Doering, K. R. S., Ermakova, G. & Taubert, S. Nuclear hormone receptor NHR-49 is an essential regulator of stress resilience and healthy aging in Caenorhabditis elegans. Front. Physiol. 14 , 1241591 (2023). 37645565 10.3389/fphys.2023.1241591 PMC10461480

352. Yang Z Targeting nuclear receptors for cancer therapy: Premises, promises, and challenges Trends Cancer 2021 7 541 556 33341430 10.1016/j.trecan.2020.11.007 Yang, Z. et al. Targeting nuclear receptors for cancer therapy: Premises, promises, and challenges. Trends Cancer 7 , 541–556 (2021). 33341430 10.1016/j.trecan.2020.11.007

353. Moutinho M Codocedo JF Puntambekar SS Landreth GE Nuclear receptors as therapeutic targets for neurodegenerative diseases: Lost in translation Annu. Rev. Pharmacol. Toxicol. 2019 59 237 261 30208281 10.1146/annurev-pharmtox-010818-021807 PMC6636329 Moutinho, M., Codocedo, J. F., Puntambekar, S. S. & Landreth, G. E. Nuclear receptors as therapeutic targets for neurodegenerative diseases: Lost in translation. Annu. Rev. Pharmacol. Toxicol. 59 , 237–261 (2019). 30208281 10.1146/annurev-pharmtox-010818-021807 PMC6636329

354. Dubois V Lefebvre P Staels B Eeckhoute J Nuclear receptors: pathophysiological mechanisms and drug targets in liver disease Gut 2024 73 1562 1569 38862216 10.1136/gutjnl-2023-331741 Dubois, V., Lefebvre, P., Staels, B. & Eeckhoute, J. Nuclear receptors: pathophysiological mechanisms and drug targets in liver disease. Gut 73 , 1562–1569 (2024). 38862216 10.1136/gutjnl-2023-331741

355. Allison KH Estrogen and progesterone receptor testing in breast cancer: ASCO/CAP guideline update J. Clin. Oncol. 2020 38 1346 1366 31928404 10.1200/JCO.19.02309 Allison, K. H. et al. Estrogen and progesterone receptor testing in breast cancer: ASCO/CAP guideline update. J. Clin. Oncol. 38 , 1346–1366 (2020). 31928404 10.1200/JCO.19.02309

356. Xu G ARID1A determines luminal identity and therapeutic response in estrogen-receptor-positive breast cancer Nat. Genet. 2020 52 198 207 31932695 10.1038/s41588-019-0554-0 PMC7341683 Xu, G. et al. ARID1A determines luminal identity and therapeutic response in estrogen-receptor-positive breast cancer. Nat. Genet. 52 , 198–207 (2020). 31932695 10.1038/s41588-019-0554-0 PMC7341683

357. González ER Estrogen, progesterone receptors in ovarian cancer JAMA 1981 245 1626 7206169 10.1001/jama.1981.03310410006003 González, E. R. Estrogen, progesterone receptors in ovarian cancer. JAMA 245 , 1626 (1981). 7206169 10.1001/jama.1981.03310410006003

358. Williams A SOX2 expression in prostate cancer drives resistance to nuclear hormone receptor signaling inhibition through the WEE1/CDK1 signaling axis Cancer Lett. 2023 565 216209 37169162 10.1016/j.canlet.2023.216209 PMC13037384 Williams, A. et al. SOX2 expression in prostate cancer drives resistance to nuclear hormone receptor signaling inhibition through the WEE1/CDK1 signaling axis. Cancer Lett. 565 , 216209 (2023). 37169162 10.1016/j.canlet.2023.216209 PMC13037384

359. Zhang J Naringenin in Si-Ni-San formula inhibits chronic psychological stress-induced breast cancer growth and metastasis by modulating estrogen metabolism through FXR/EST pathway J. Adv. Res 2023 47 189 207 35718080 10.1016/j.jare.2022.06.006 PMC10173160 Zhang, J. et al. Naringenin in Si-Ni-San formula inhibits chronic psychological stress-induced breast cancer growth and metastasis by modulating estrogen metabolism through FXR/EST pathway. J. Adv. Res . 47 , 189–207 (2023). 35718080 10.1016/j.jare.2022.06.006 PMC10173160

360. Zhao L Zhou S Gustafsson J Nuclear receptors: Recent drug discovery for cancer therapies Endocr. Rev. 2019 40 1207 1249 30869771 10.1210/er.2018-00222 Zhao, L., Zhou, S. & Gustafsson, J. Nuclear receptors: Recent drug discovery for cancer therapies. Endocr. Rev. 40 , 1207–1249 (2019). 30869771 10.1210/er.2018-00222

361. Dierickx P Circadian REV-ERBs repress E4bp4 to activate NAMPT-dependent NAD(+) biosynthesis and sustain cardiac function Nat. Cardiovasc Res 2022 1 45 58 35036997 10.1038/s44161-021-00001-9 PMC8754391 Dierickx, P. et al. Circadian REV-ERBs repress E4bp4 to activate NAMPT-dependent NAD(+) biosynthesis and sustain cardiac function. Nat. Cardiovasc Res 1 , 45–58 (2022). 35036997 10.1038/s44161-021-00001-9 PMC8754391

362. van Weelden WJ Massuger L Pijnenborg JMA Romano A Anti-estrogen treatment in endometrial cancer: A systematic review Front. Oncol. 2019 9 359 31134155 10.3389/fonc.2019.00359 PMC6513972 van Weelden, W. J., Massuger, L., Pijnenborg, J. M. A. & Romano, A. Anti-estrogen treatment in endometrial cancer: A systematic review. Front. Oncol. 9 , 359 (2019). 31134155 10.3389/fonc.2019.00359 PMC6513972

363. Patel HK Bihani T Selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs) in cancer treatment Pharmacol. Ther. 2018 186 1 24 29289555 10.1016/j.pharmthera.2017.12.012 Patel, H. K. & Bihani, T. Selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs) in cancer treatment. Pharmacol. Ther. 186 , 1–24 (2018). 29289555 10.1016/j.pharmthera.2017.12.012

364. Miki Y Suzuki T Sasano H Aromatase inhibitor and bone Biomed. Pharmacother. 2007 61 540 542 17904790 10.1016/j.biopha.2007.08.011 Miki, Y., Suzuki, T. & Sasano, H. Aromatase inhibitor and bone. Biomed. Pharmacother. 61 , 540–542 (2007). 17904790 10.1016/j.biopha.2007.08.011

365. Tian Y MIR497HG-Derived miR-195 and miR-497 mediate tamoxifen resistance via PI3K/AKT signaling in breast cancer Adv. Sci. (Weinh.) 2023 10 e2204819 36815359 10.1002/advs.202204819 PMC10131819 Tian, Y. et al. MIR497HG-Derived miR-195 and miR-497 mediate tamoxifen resistance via PI3K/AKT signaling in breast cancer. Adv. Sci. (Weinh.) 10 , e2204819 (2023). 36815359 10.1002/advs.202204819 PMC10131819

366. Gao Y CD63(+) cancer-associated fibroblasts confer tamoxifen resistance to breast cancer cells through exosomal miR-22 Adv. Sci. (Weinh.) 2020 7 2002518 33173749 10.1002/advs.202002518 PMC7610308 Gao, Y. et al. CD63(+) cancer-associated fibroblasts confer tamoxifen resistance to breast cancer cells through exosomal miR-22. Adv. Sci. (Weinh.) 7 , 2002518 (2020). 33173749 10.1002/advs.202002518 PMC7610308

367. Woolas J Davis M Rahimi S Recurrence of endometrial cancer in a hysterectomised patient treated with tamoxifen for breast cancer: A case report J. R. Soc. Med. 2020 113 454 456 33044110 10.1177/0141076820961087 PMC7686519 Woolas, J., Davis, M. & Rahimi, S. Recurrence of endometrial cancer in a hysterectomised patient treated with tamoxifen for breast cancer: A case report. J. R. Soc. Med. 113 , 454–456 (2020). 33044110 10.1177/0141076820961087 PMC7686519

368. Trédan O Regorafenib or Tamoxifen for platinum-sensitive recurrent ovarian cancer with rising CA125 and no evidence of clinical or RECIST progression: A GINECO randomized phase II trial (REGOVAR) Gynecol. Oncol. 2022 164 18 26 34696892 10.1016/j.ygyno.2021.10.012 PMC9753595 Trédan, O. et al. Regorafenib or Tamoxifen for platinum-sensitive recurrent ovarian cancer with rising CA125 and no evidence of clinical or RECIST progression: A GINECO randomized phase II trial (REGOVAR). Gynecol. Oncol. 164 , 18–26 (2022). 34696892 10.1016/j.ygyno.2021.10.012 PMC9753595

369. Bonkhoff H Estrogen receptor signaling in prostate cancer: Implications for carcinogenesis and tumor progression Prostate 2018 78 2 10 29094395 10.1002/pros.23446 Bonkhoff, H. Estrogen receptor signaling in prostate cancer: Implications for carcinogenesis and tumor progression. Prostate 78 , 2–10 (2018). 29094395 10.1002/pros.23446

370. Qu LG Effects of estrogen receptor signaling on prostate cancer carcinogenesis Transl. Res. 2020 222 56 66 32413498 10.1016/j.trsl.2020.04.003 Qu, L. G. et al. Effects of estrogen receptor signaling on prostate cancer carcinogenesis. Transl. Res. 222 , 56–66 (2020). 32413498 10.1016/j.trsl.2020.04.003

371. Yu EY Selective estrogen receptor alpha agonist GTx-758 decreases testosterone with reduced side effects of androgen deprivation therapy in men with advanced prostate cancer Eur. Urol. 2015 67 334 341 24968970 10.1016/j.eururo.2014.06.011 Yu, E. Y. et al. Selective estrogen receptor alpha agonist GTx-758 decreases testosterone with reduced side effects of androgen deprivation therapy in men with advanced prostate cancer. Eur. Urol. 67 , 334–341 (2015). 24968970 10.1016/j.eururo.2014.06.011

372. Huang J Lin B Li B Anti-androgen receptor therapies in prostate cancer: A brief update and perspective Front. Oncol. 2022 12 865350 35372068 10.3389/fonc.2022.865350 PMC8965587 Huang, J., Lin, B. & Li, B. Anti-androgen receptor therapies in prostate cancer: A brief update and perspective. Front. Oncol. 12 , 865350 (2022). 35372068 10.3389/fonc.2022.865350 PMC8965587

373. Waltering KK Increased expression of androgen receptor sensitizes prostate cancer cells to low levels of androgens Cancer Res. 2009 69 8141 8149 19808968 10.1158/0008-5472.CAN-09-0919 Waltering, K. K. et al. Increased expression of androgen receptor sensitizes prostate cancer cells to low levels of androgens. Cancer Res. 69 , 8141–8149 (2009). 19808968 10.1158/0008-5472.CAN-09-0919

374. Fizazi K Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2 × 2 factorial design Lancet 2022 399 1695 1707 35405085 10.1016/S0140-6736(22)00367-1 Fizazi, K. et al. Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2 × 2 factorial design. Lancet 399 , 1695–1707 (2022). 35405085 10.1016/S0140-6736(22)00367-1

375. Hong, F. et al. PPARs as nuclear receptors for nutrient and energy metabolism. Molecules . 24 , (2019). 10.3390/molecules24142545 PMC6680900 31336903

376. Hu P Nuclear receptor PPARα as a therapeutic target in diseases associated with lipid metabolism disorders Nutrients 2023 15 4772 38004166 10.3390/nu15224772 PMC10674366 Hu, P. et al. Nuclear receptor PPARα as a therapeutic target in diseases associated with lipid metabolism disorders. Nutrients 15 , 4772 (2023). 38004166 10.3390/nu15224772 PMC10674366

377. Colucci M Retinoic acid receptor activation reprograms senescence response and enhances anti-tumor activity of natural killer cells Cancer Cell 2024 42 646 661.e649 38428412 10.1016/j.ccell.2024.02.004 PMC11003464 Colucci, M. et al. Retinoic acid receptor activation reprograms senescence response and enhances anti-tumor activity of natural killer cells. Cancer Cell 42 , 646–661.e649 (2024). 38428412 10.1016/j.ccell.2024.02.004 PMC11003464

378. Sulli G Pharmacological activation of REV-ERBs is lethal in cancer and oncogene-induced senescence Nature 2018 553 351 355 29320480 10.1038/nature25170 PMC5924733 Sulli, G. et al. Pharmacological activation of REV-ERBs is lethal in cancer and oncogene-induced senescence. Nature 553 , 351–355 (2018). 29320480 10.1038/nature25170 PMC5924733

379. Lonardo, A., Leoni, S., Alswat, K. A. & Fouad, Y. History of nonalcoholic fatty liver disease. Int. J. Mol. Sci . 21 , (2020). 10.3390/ijms21165888 PMC7460697 32824337

380. Schulman IG Nuclear receptors as drug targets for metabolic disease Adv. Drug Deliv. Rev. 2010 62 1307 1315 20655343 10.1016/j.addr.2010.07.002 PMC2987515 Schulman, I. G. Nuclear receptors as drug targets for metabolic disease. Adv. Drug Deliv. Rev. 62 , 1307–1315 (2010). 20655343 10.1016/j.addr.2010.07.002 PMC2987515

381. Mitrovic B Non-alcoholic fatty liver disease, metabolic syndrome, and type 2 diabetes mellitus: where do we stand today? Arch. Med. Sci. 2023 19 884 894 37560721 10.5114/aoms/150639 PMC10408022 Mitrovic, B. et al. Non-alcoholic fatty liver disease, metabolic syndrome, and type 2 diabetes mellitus: where do we stand today?. Arch. Med. Sci. 19 , 884–894 (2023). 37560721 10.5114/aoms/150639 PMC10408022

382. Genua I Cusi K Pharmacological approaches to nonalcoholic fatty liver disease: Current and future therapies Diab. Spectr. 2024 37 48 58 10.2337/dsi23-0012 PMC10877217 38385098 Genua, I. & Cusi, K. Pharmacological approaches to nonalcoholic fatty liver disease: Current and future therapies. Diab. Spectr. 37 , 48–58 (2024). 10.2337/dsi23-0012 PMC10877217 38385098

383. Ali AH Lipid-lowering therapies for atherosclerosis: Statins, fibrates, ezetimibe and PCSK9 monoclonal antibodies Curr. Med. Chem. 2021 28 7427 7445 33655822 10.2174/0929867328666210222092628 Ali, A. H. et al. Lipid-lowering therapies for atherosclerosis: Statins, fibrates, ezetimibe and PCSK9 monoclonal antibodies. Curr. Med. Chem. 28 , 7427–7445 (2021). 33655822 10.2174/0929867328666210222092628

384. Yamashita S Masuda D Matsuzawa Y Pemafibrate, a new selective PPARα modulator: Drug concept and its clinical applications for dyslipidemia and metabolic diseases Curr. Atheroscler. Rep. 2020 22 5 31974794 10.1007/s11883-020-0823-5 PMC6978439 Yamashita, S., Masuda, D. & Matsuzawa, Y. Pemafibrate, a new selective PPARα modulator: Drug concept and its clinical applications for dyslipidemia and metabolic diseases. Curr. Atheroscler. Rep. 22 , 5 (2020). 31974794 10.1007/s11883-020-0823-5 PMC6978439

385. Yamashita S Effects of pemafibrate (K-877) on cholesterol efflux capacity and postprandial hyperlipidemia in patients with atherogenic dyslipidemia J. Clin. Lipidol. 2018 12 1267 1279.e1264 30077640 10.1016/j.jacl.2018.06.010 Yamashita, S. et al. Effects of pemafibrate (K-877) on cholesterol efflux capacity and postprandial hyperlipidemia in patients with atherogenic dyslipidemia. J. Clin. Lipidol. 12 , 1267–1279.e1264 (2018). 30077640 10.1016/j.jacl.2018.06.010

386. Araki E Effects of pemafibrate, a novel selective PPARα modulator, on lipid and glucose metabolism in patients with type 2 diabetes and hypertriglyceridemia: A randomized, double-blind, placebo-controlled, phase 3 trial Diab. Care 2018 41 538 546 10.2337/dc17-1589 29298800 Araki, E. et al. Effects of pemafibrate, a novel selective PPARα modulator, on lipid and glucose metabolism in patients with type 2 diabetes and hypertriglyceridemia: A randomized, double-blind, placebo-controlled, phase 3 trial. Diab. Care 41 , 538–546 (2018). 10.2337/dc17-1589 29298800

387. Shannon CE Insulin resistance is mechanistically linked to hepatic mitochondrial remodeling in non-alcoholic fatty liver disease Mol. Metab. 2021 45 101154 33359401 10.1016/j.molmet.2020.101154 PMC7811046 Shannon, C. E. et al. Insulin resistance is mechanistically linked to hepatic mitochondrial remodeling in non-alcoholic fatty liver disease. Mol. Metab. 45 , 101154 (2021). 33359401 10.1016/j.molmet.2020.101154 PMC7811046

388. Della-Morte D Pharmacogenomics and pharmacogenetics of thiazolidinediones: role in diabetes and cardiovascular risk factors Pharmacogenomics 2014 15 2063 2082 25521362 10.2217/pgs.14.162 PMC4314213 Della-Morte, D. et al. Pharmacogenomics and pharmacogenetics of thiazolidinediones: role in diabetes and cardiovascular risk factors. Pharmacogenomics 15 , 2063–2082 (2014). 25521362 10.2217/pgs.14.162 PMC4314213

389. Adorini L Trauner M FXR agonists in NASH treatment J. Hepatol. 2023 79 1317 1331 37562746 10.1016/j.jhep.2023.07.034 Adorini, L. & Trauner, M. FXR agonists in NASH treatment. J. Hepatol. 79 , 1317–1331 (2023). 37562746 10.1016/j.jhep.2023.07.034

390. Stofan, M. & Guo, G. L. Bile acids and FXR: Novel targets for liver diseases. Front. Med . 7 , (2020). 10.3389/fmed.2020.00544 PMC7516013 33015098

391. Yang S Ginsenoside Rh4 improves hepatic lipid metabolism and inflammation in a model of NAFLD by targeting the gut liver axis and modulating the FXR signaling pathway Foods 2023 12 2492 37444230 10.3390/foods12132492 PMC10341168 Yang, S. et al. Ginsenoside Rh4 improves hepatic lipid metabolism and inflammation in a model of NAFLD by targeting the gut liver axis and modulating the FXR signaling pathway. Foods 12 , 2492 (2023). 37444230 10.3390/foods12132492 PMC10341168

392. Younossi ZM Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial Lancet 2019 394 2184 2196 31813633 10.1016/S0140-6736(19)33041-7 Younossi, Z. M. et al. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 394 , 2184–2196 (2019). 31813633 10.1016/S0140-6736(19)33041-7

393. Ratziu V EDP-305 in patients with NASH: A phase II double-blind placebo-controlled dose-ranging study J. Hepatol. 2022 76 506 517 34740705 10.1016/j.jhep.2021.10.018 Ratziu, V. et al. EDP-305 in patients with NASH: A phase II double-blind placebo-controlled dose-ranging study. J. Hepatol. 76 , 506–517 (2022). 34740705 10.1016/j.jhep.2021.10.018

394. El Kasmi KC Pharmacologic activation of hepatic farnesoid X receptor prevents parenteral nutrition-associated cholestasis in mice Hepatology 2022 75 252 265 34387888 10.1002/hep.32101 El Kasmi, K. C. et al. Pharmacologic activation of hepatic farnesoid X receptor prevents parenteral nutrition-associated cholestasis in mice. Hepatology 75 , 252–265 (2022). 34387888 10.1002/hep.32101

395. Hernández-Hernández I Endogenous LXR signaling controls pulmonary surfactant homeostasis and prevents lung inflammation Cell. Mol. Life Sci. 2024 81 287 38970705 10.1007/s00018-024-05310-3 PMC11335212 Hernández-Hernández, I. et al. Endogenous LXR signaling controls pulmonary surfactant homeostasis and prevents lung inflammation. Cell. Mol. Life Sci. 81 , 287 (2024). 38970705 10.1007/s00018-024-05310-3 PMC11335212

396. Zhao Y Disruption of circadian rhythms by shift work exacerbates reperfusion injury in myocardial infarction J. Am. Coll. Cardiol. 2022 79 2097 2115 35618347 10.1016/S0735-1097(22)03088-1 PMC8972444 Zhao, Y. et al. Disruption of circadian rhythms by shift work exacerbates reperfusion injury in myocardial infarction. J. Am. Coll. Cardiol. 79 , 2097–2115 (2022). 35618347 10.1016/S0735-1097(22)03088-1 PMC8972444

397. Pourcet, B. & Duez, H. Nuclear receptors and clock components in cardiovascular diseases. Int. J. Mol. Sci . 22 , (2021). 10.3390/ijms22189721 PMC8468608 34575881

398. Griffett K Antihyperlipidemic activity of gut-restricted LXR inverse agonists ACS Chem. Biol. 2022 17 1143 1154 35417135 10.1021/acschembio.2c00057 Griffett, K. et al. Antihyperlipidemic activity of gut-restricted LXR inverse agonists. ACS Chem. Biol. 17 , 1143–1154 (2022). 35417135 10.1021/acschembio.2c00057

399. Kim EJ RORα suppresses proliferation of vascular smooth muscle cells through activation of AMP-activated protein kinase Int. J. Cardiol. 2014 175 515 521 25017905 10.1016/j.ijcard.2014.06.043 Kim, E. J. et al. RORα suppresses proliferation of vascular smooth muscle cells through activation of AMP-activated protein kinase. Int. J. Cardiol. 175 , 515–521 (2014). 25017905 10.1016/j.ijcard.2014.06.043

400. Ling S Natural compound bavachalcone promotes the differentiation of endothelial progenitor cells and neovascularization through the RORα-erythropoietin-AMPK axis Oncotarget 2017 8 86188 86205 29156787 10.18632/oncotarget.21036 PMC5689677 Ling, S. et al. Natural compound bavachalcone promotes the differentiation of endothelial progenitor cells and neovascularization through the RORα-erythropoietin-AMPK axis. Oncotarget 8 , 86188–86205 (2017). 29156787 10.18632/oncotarget.21036 PMC5689677

401. Huang H Melatonin prevents endothelial dysfunction in SLE by activating the nuclear receptor retinoic acid-related orphan receptor-α Int. Immunopharmacol. 2020 83 106365 32172204 10.1016/j.intimp.2020.106365 Huang, H. et al. Melatonin prevents endothelial dysfunction in SLE by activating the nuclear receptor retinoic acid-related orphan receptor-α. Int. Immunopharmacol. 83 , 106365 (2020). 32172204 10.1016/j.intimp.2020.106365

402. Ding S Melatonin stabilizes rupture-prone vulnerable plaques via regulating macrophage polarization in a nuclear circadian receptor RORα-dependent manner J. Pineal Res. 2019 67 e12581 31009101 10.1111/jpi.12581 Ding, S. et al. Melatonin stabilizes rupture-prone vulnerable plaques via regulating macrophage polarization in a nuclear circadian receptor RORα-dependent manner. J. Pineal Res. 67 , e12581 (2019). 31009101 10.1111/jpi.12581

403. Peliciari-Garcia RA Expression of circadian clock and melatonin receptors within cultured rat cardiomyocytes Chronobiol. Int 2011 28 21 30 21182401 10.3109/07420528.2010.525675 Peliciari-Garcia, R. A. et al. Expression of circadian clock and melatonin receptors within cultured rat cardiomyocytes. Chronobiol. Int 28 , 21–30 (2011). 21182401 10.3109/07420528.2010.525675

404. Chang HY Tain YL Postnatal dexamethasone-induced programmed hypertension is related to the regulation of melatonin and its receptors Steroids 2016 108 1 6 26921678 10.1016/j.steroids.2016.02.017 Chang, H. Y. & Tain, Y. L. Postnatal dexamethasone-induced programmed hypertension is related to the regulation of melatonin and its receptors. Steroids 108 , 1–6 (2016). 26921678 10.1016/j.steroids.2016.02.017

405. Hong H REV-ERBα agonist SR9009 suppresses IL-1β production in macrophages through BMAL1-dependent inhibition of inflammasome Biochem Pharm. 2021 192 114701 34324866 10.1016/j.bcp.2021.114701 Hong, H. et al. REV-ERBα agonist SR9009 suppresses IL-1β production in macrophages through BMAL1-dependent inhibition of inflammasome. Biochem Pharm. 192 , 114701 (2021). 34324866 10.1016/j.bcp.2021.114701

406. Grant D GSK4112, a small molecule chemical probe for the cell biology of the nuclear heme receptor Rev-erbα ACS Chem. Biol. 2010 5 925 932 20677822 10.1021/cb100141y Grant, D. et al. GSK4112, a small molecule chemical probe for the cell biology of the nuclear heme receptor Rev-erbα. ACS Chem. Biol. 5 , 925–932 (2010). 20677822 10.1021/cb100141y

407. Shan P RXR agonists inhibit oxidative stress-induced apoptosis in H9c2 rat ventricular cells Biochem Biophys. Res Commun. 2008 375 628 633 18755147 10.1016/j.bbrc.2008.08.074 Shan, P. et al. RXR agonists inhibit oxidative stress-induced apoptosis in H9c2 rat ventricular cells. Biochem Biophys. Res Commun. 375 , 628–633 (2008). 18755147 10.1016/j.bbrc.2008.08.074

408. Lehman AM Activation of the retinoid X receptor modulates angiotensin II-induced smooth muscle gene expression and inflammation in vascular smooth muscle cells Mol. Pharm. 2014 86 570 579 10.1124/mol.114.092163 PMC4201143 25169989 Lehman, A. M. et al. Activation of the retinoid X receptor modulates angiotensin II-induced smooth muscle gene expression and inflammation in vascular smooth muscle cells. Mol. Pharm. 86 , 570–579 (2014). 10.1124/mol.114.092163 PMC4201143 25169989

409. Xu W Novel Pan-ERR agonists ameliorate heart failure through enhancing cardiac fatty acid metabolism and mitochondrial function Circulation 2024 149 227 250 37961903 10.1161/CIRCULATIONAHA.123.066542 PMC10842599 Xu, W. et al. Novel Pan-ERR agonists ameliorate heart failure through enhancing cardiac fatty acid metabolism and mitochondrial function. Circulation 149 , 227–250 (2024). 37961903 10.1161/CIRCULATIONAHA.123.066542 PMC10842599

410. Nakajima Y Retinoic acid signaling in heart development Genesis 2019 57 e23300 31021052 10.1002/dvg.23300 Nakajima, Y. Retinoic acid signaling in heart development. Genesis 57 , e23300 (2019). 31021052 10.1002/dvg.23300

411. Wang S Retinoic acid signaling promotes the cytoskeletal rearrangement of embryonic epicardial cells FASEB J. 2018 32 3765 3781 29447006 10.1096/fj.201701038R PMC5998982 Wang, S. et al. Retinoic acid signaling promotes the cytoskeletal rearrangement of embryonic epicardial cells. FASEB J. 32 , 3765–3781 (2018). 29447006 10.1096/fj.201701038R PMC5998982

412. Jamwal S Blackburn JK Elsworth JD PPARγ/PGC1α signaling as a potential therapeutic target for mitochondrial biogenesis in neurodegenerative disorders Pharmacol. Ther. 2021 219 107705 33039420 10.1016/j.pharmthera.2020.107705 PMC7887032 Jamwal, S., Blackburn, J. K. & Elsworth, J. D. PPARγ/PGC1α signaling as a potential therapeutic target for mitochondrial biogenesis in neurodegenerative disorders. Pharmacol. Ther. 219 , 107705 (2021). 33039420 10.1016/j.pharmthera.2020.107705 PMC7887032

413. Tufano, M. & Pinna, G. Is there a future for PPARs in the treatment of neuropsychiatric disorders? Molecules . 25 , (2020). 10.3390/molecules25051062 PMC7179196 32120979

414. Ghosh C Modulation of glucocorticoid receptor in human epileptic endothelial cells impacts drug biotransformation in an in vitro blood-brain barrier model Epilepsia 2018 59 2049 2060 30264400 10.1111/epi.14567 PMC6282717 Ghosh, C. et al. Modulation of glucocorticoid receptor in human epileptic endothelial cells impacts drug biotransformation in an in vitro blood-brain barrier model. Epilepsia 59 , 2049–2060 (2018). 30264400 10.1111/epi.14567 PMC6282717

415. Ghosh C Overexpression of pregnane X and glucocorticoid receptors and the regulation of cytochrome P450 in human epileptic brain endothelial cells Epilepsia 2017 58 576 585 28199000 10.1111/epi.13703 PMC5386820 Ghosh, C. et al. Overexpression of pregnane X and glucocorticoid receptors and the regulation of cytochrome P450 in human epileptic brain endothelial cells. Epilepsia 58 , 576–585 (2017). 28199000 10.1111/epi.13703 PMC5386820

416. Tertil M Glucocorticoid receptor signaling in astrocytes is required for aversive memory formation Transl. Psychiatry 2018 8 255 30487639 10.1038/s41398-018-0300-x PMC6261947 Tertil, M. et al. Glucocorticoid receptor signaling in astrocytes is required for aversive memory formation. Transl. Psychiatry 8 , 255 (2018). 30487639 10.1038/s41398-018-0300-x PMC6261947

417. Hartmann J Forebrain glutamatergic, but not GABAergic, neurons mediate anxiogenic effects of the glucocorticoid receptor Mol. Psychiatry 2017 22 466 475 27240530 10.1038/mp.2016.87 Hartmann, J. et al. Forebrain glutamatergic, but not GABAergic, neurons mediate anxiogenic effects of the glucocorticoid receptor. Mol. Psychiatry 22 , 466–475 (2017). 27240530 10.1038/mp.2016.87

418. McKlveen JM Role of prefrontal cortex glucocorticoid receptors in stress and emotion Biol. Psychiatry 2013 74 672 679 23683655 10.1016/j.biopsych.2013.03.024 PMC3797253 McKlveen, J. M. et al. Role of prefrontal cortex glucocorticoid receptors in stress and emotion. Biol. Psychiatry 74 , 672–679 (2013). 23683655 10.1016/j.biopsych.2013.03.024 PMC3797253

419. Baes C Martins CM Tofoli SM Juruena MF Early life stress in depressive patients: HPA axis response to GR and MR agonist Front Psychiatry 2014 5 2 24478730 10.3389/fpsyt.2014.00002 PMC3900767 Baes, C., Martins, C. M., Tofoli, S. M. & Juruena, M. F. Early life stress in depressive patients: HPA axis response to GR and MR agonist. Front Psychiatry 5 , 2 (2014). 24478730 10.3389/fpsyt.2014.00002 PMC3900767

420. Hue CD Dexamethasone potentiates in vitro blood-brain barrier recovery after primary blast injury by glucocorticoid receptor-mediated upregulation of ZO-1 tight junction protein J. Cereb. Blood Flow. Metab. 2015 35 1191 1198 25757751 10.1038/jcbfm.2015.38 PMC4640274 Hue, C. D. et al. Dexamethasone potentiates in vitro blood-brain barrier recovery after primary blast injury by glucocorticoid receptor-mediated upregulation of ZO-1 tight junction protein. J. Cereb. Blood Flow. Metab. 35 , 1191–1198 (2015). 25757751 10.1038/jcbfm.2015.38 PMC4640274

421. Tsai HC Dexamethasone inhibits brain apoptosis in mice with eosinophilic meningitis caused by Angiostrongylus cantonensis infection Parasit. Vectors 2015 8 200 25890054 10.1186/s13071-015-0792-7 PMC4382933 Tsai, H. C. et al. Dexamethasone inhibits brain apoptosis in mice with eosinophilic meningitis caused by Angiostrongylus cantonensis infection. Parasit. Vectors 8 , 200 (2015). 25890054 10.1186/s13071-015-0792-7 PMC4382933

422. de Vargas LDS Methylprednisolone as a memory enhancer in rats: Effects on aversive memory, long-term potentiation and calcium influx Brain Res. 2017 1670 44 51 28606783 10.1016/j.brainres.2017.06.007 de Vargas, L. D. S. et al. Methylprednisolone as a memory enhancer in rats: Effects on aversive memory, long-term potentiation and calcium influx. Brain Res. 1670 , 44–51 (2017). 28606783 10.1016/j.brainres.2017.06.007

423. Dos Santos N High dose of dexamethasone protects against EAE-induced motor deficits but impairs learning/memory in C57BL/6 mice Sci. Rep. 2019 9 6673 31040362 10.1038/s41598-019-43217-3 PMC6491620 Dos Santos, N. et al. High dose of dexamethasone protects against EAE-induced motor deficits but impairs learning/memory in C57BL/6 mice. Sci. Rep. 9 , 6673 (2019). 31040362 10.1038/s41598-019-43217-3 PMC6491620

424. Baglietto-Vargas D Mifepristone alters amyloid precursor protein processing to preclude amyloid beta and also reduces tau pathology Biol. Psychiatry 2013 74 357 366 23312564 10.1016/j.biopsych.2012.12.003 PMC3633722 Baglietto-Vargas, D. et al. Mifepristone alters amyloid precursor protein processing to preclude amyloid beta and also reduces tau pathology. Biol. Psychiatry 74 , 357–366 (2013). 23312564 10.1016/j.biopsych.2012.12.003 PMC3633722

425. Nguyen ET A mixed glucocorticoid/mineralocorticoid receptor modulator dampens endocrine and hippocampal stress responsivity in male rats Physiol. Behav. 2017 178 82 92 28093219 10.1016/j.physbeh.2017.01.020 PMC5511095 Nguyen, E. T. et al. A mixed glucocorticoid/mineralocorticoid receptor modulator dampens endocrine and hippocampal stress responsivity in male rats. Physiol. Behav. 178 , 82–92 (2017). 28093219 10.1016/j.physbeh.2017.01.020 PMC5511095

426. He Y Protective effect of Nr4a2 (Nurr1) against LPS-induced depressive-like behaviors via regulating activity of microglia and CamkII neurons in anterior cingulate cortex Pharmacol. Res. 2023 191 106717 36948326 10.1016/j.phrs.2023.106717 He, Y. et al. Protective effect of Nr4a2 (Nurr1) against LPS-induced depressive-like behaviors via regulating activity of microglia and CamkII neurons in anterior cingulate cortex. Pharmacol. Res. 191 , 106717 (2023). 36948326 10.1016/j.phrs.2023.106717

427. Zhang LM Dopamine agonists Exert Nurr1-inducing effect in peripheral blood mononuclear cells of patients with Parkinson’s disease Chin. Med. J. (Engl.). 2015 128 1755 1760 26112716 10.4103/0366-6999.159349 PMC4733729 Zhang, L. M. et al. Dopamine agonists Exert Nurr1-inducing effect in peripheral blood mononuclear cells of patients with Parkinson’s disease. Chin. Med. J. (Engl.). 128 , 1755–1760 (2015). 26112716 10.4103/0366-6999.159349 PMC4733729

428. Wu Y Activation of the bile acid receptors TGR5 and FXR in the spinal dorsal horn alleviates neuropathic pain CNS Neurosci. Ther. 2023 29 1981 1998 36880297 10.1111/cns.14154 PMC10324360 Wu, Y. et al. Activation of the bile acid receptors TGR5 and FXR in the spinal dorsal horn alleviates neuropathic pain. CNS Neurosci. Ther. 29 , 1981–1998 (2023). 36880297 10.1111/cns.14154 PMC10324360

429. Mohammadzadeh Honarvar N The effect of vitamin A supplementation on retinoic acid-related orphan receptor γt (RORγt) and interleukin-17 (IL-17) gene expression in Avonex-treated multiple sclerotic patients J. Mol. Neurosci. 2013 51 749 753 23868508 10.1007/s12031-013-0058-9 Mohammadzadeh Honarvar, N. et al. The effect of vitamin A supplementation on retinoic acid-related orphan receptor γt (RORγt) and interleukin-17 (IL-17) gene expression in Avonex-treated multiple sclerotic patients. J. Mol. Neurosci. 51 , 749–753 (2013). 23868508 10.1007/s12031-013-0058-9

430. Leopold Wager CM Arnett E Schlesinger LS Macrophage nuclear receptors: Emerging key players in infectious diseases PLoS Pathog. 2019 15 e1007585 30897154 10.1371/journal.ppat.1007585 PMC6428245 Leopold Wager, C. M., Arnett, E. & Schlesinger, L. S. Macrophage nuclear receptors: Emerging key players in infectious diseases. PLoS Pathog. 15 , e1007585 (2019). 30897154 10.1371/journal.ppat.1007585 PMC6428245

431. Levy G Nuclear receptors control pro-viral and antiviral metabolic responses to hepatitis C virus infection Nat. Chem. Biol. 2016 12 1037 1045 27723751 10.1038/nchembio.2193 PMC7046487 Levy, G. et al. Nuclear receptors control pro-viral and antiviral metabolic responses to hepatitis C virus infection. Nat. Chem. Biol. 12 , 1037–1045 (2016). 27723751 10.1038/nchembio.2193 PMC7046487

432. Liu HM Lee TY Liao JF GW4064 attenuates lipopolysaccharide‑induced hepatic inflammation and apoptosis through inhibition of the Toll‑like receptor 4‑mediated p38 mitogen‑activated protein kinase signaling pathway in mice Int. J. Mol. Med. 2018 41 1455 1462 29328388 10.3892/ijmm.2018.3366 PMC5819900 Liu, H. M., Lee, T. Y. & Liao, J. F. GW4064 attenuates lipopolysaccharide‑induced hepatic inflammation and apoptosis through inhibition of the Toll‑like receptor 4‑mediated p38 mitogen‑activated protein kinase signaling pathway in mice. Int. J. Mol. Med. 41 , 1455–1462 (2018). 29328388 10.3892/ijmm.2018.3366 PMC5819900

433. Hu YB Liu XY Zhan W Farnesoid X receptor agonist INT-767 attenuates liver steatosis and inflammation in rat model of nonalcoholic steatohepatitis Drug Des. Devel. Ther. 2018 12 2213 2221 30038487 10.2147/DDDT.S170518 PMC6052932 Hu, Y. B., Liu, X. Y. & Zhan, W. Farnesoid X receptor agonist INT-767 attenuates liver steatosis and inflammation in rat model of nonalcoholic steatohepatitis. Drug Des. Devel. Ther. 12 , 2213–2221 (2018). 30038487 10.2147/DDDT.S170518 PMC6052932

434. Wu ZY Farnesoid X receptor agonist GW4064 indirectly inhibits HCV entry into cells via down-regulating scavenger receptor class B type I Eur. J. Pharm. 2019 853 111 120 10.1016/j.ejphar.2019.03.033 30902657 Wu, Z. Y. et al. Farnesoid X receptor agonist GW4064 indirectly inhibits HCV entry into cells via down-regulating scavenger receptor class B type I. Eur. J. Pharm. 853 , 111–120 (2019). 10.1016/j.ejphar.2019.03.033 30902657

435. Thurlow LR Joshi GS Richardson AR Peroxisome proliferator-activated receptor γ is essential for the resolution of staphylococcus aureus skin infections Cell Host Microbe 2018 24 261 270.e264 30057172 10.1016/j.chom.2018.07.001 Thurlow, L. R., Joshi, G. S. & Richardson, A. R. Peroxisome proliferator-activated receptor γ is essential for the resolution of staphylococcus aureus skin infections. Cell Host Microbe 24 , 261–270.e264 (2018). 30057172 10.1016/j.chom.2018.07.001

436. Fernandez-Boyanapalli RF Pioglitazone restores phagocyte mitochondrial oxidants and bactericidal capacity in chronic granulomatous disease J. Allergy Clin. Immunol. 2015 135 517 527.e512 25498313 10.1016/j.jaci.2014.10.034 PMC4331116 Fernandez-Boyanapalli, R. F. et al. Pioglitazone restores phagocyte mitochondrial oxidants and bactericidal capacity in chronic granulomatous disease. J. Allergy Clin. Immunol. 135 , 517–527.e512 (2015). 25498313 10.1016/j.jaci.2014.10.034 PMC4331116

437. Han S Liver X receptor agonist therapy prevents diffuse alveolar hemorrhage in murine lupus by repolarizing macrophages Front. Immunol. 2018 9 135 29456535 10.3389/fimmu.2018.00135 PMC5801423 Han, S. et al. Liver X receptor agonist therapy prevents diffuse alveolar hemorrhage in murine lupus by repolarizing macrophages. Front. Immunol. 9 , 135 (2018). 29456535 10.3389/fimmu.2018.00135 PMC5801423

438. Matalonga J The nuclear receptor LXR limits bacterial infection of host macrophages through a mechanism that impacts cellular NAD metabolism Cell Rep. 2017 18 1241 1255 28147278 10.1016/j.celrep.2017.01.007 Matalonga, J. et al. The nuclear receptor LXR limits bacterial infection of host macrophages through a mechanism that impacts cellular NAD metabolism. Cell Rep. 18 , 1241–1255 (2017). 28147278 10.1016/j.celrep.2017.01.007

439. Sierra B OSBPL10, RXRA and lipid metabolism confer African-ancestry protection against dengue haemorrhagic fever in admixed Cubans PLoS Pathog. 2017 13 e1006220 28241052 10.1371/journal.ppat.1006220 PMC5344536 Sierra, B. et al. OSBPL10, RXRA and lipid metabolism confer African-ancestry protection against dengue haemorrhagic fever in admixed Cubans. PLoS Pathog. 13 , e1006220 (2017). 28241052 10.1371/journal.ppat.1006220 PMC5344536

440. Lith SC Nuclear receptor Nur77 regulates immunomechanics of macrophages Eur. J. Cell Biol. 2024 103 151419 38763048 10.1016/j.ejcb.2024.151419 Lith, S. C. et al. Nuclear receptor Nur77 regulates immunomechanics of macrophages. Eur. J. Cell Biol. 103 , 151419 (2024). 38763048 10.1016/j.ejcb.2024.151419

441. Saini A An accord of nuclear receptor expression in M. tuberculosis infected macrophages and dendritic cells Sci. Rep. 2018 8 2296 29396519 10.1038/s41598-018-20769-4 PMC5797181 Saini, A. et al. An accord of nuclear receptor expression in M. tuberculosis infected macrophages and dendritic cells. Sci. Rep. 8 , 2296 (2018). 29396519 10.1038/s41598-018-20769-4 PMC5797181

442. Bhagyaraj E A human xenobiotic nuclear receptor contributes to nonresponsiveness of Mycobacterium tuberculosis to the antituberculosis drug rifampicin J. Biol. Chem. 2018 293 3747 3757 29358328 10.1074/jbc.M117.818377 PMC5846149 Bhagyaraj, E. et al. A human xenobiotic nuclear receptor contributes to nonresponsiveness of Mycobacterium tuberculosis to the antituberculosis drug rifampicin. J. Biol. Chem. 293 , 3747–3757 (2018). 29358328 10.1074/jbc.M117.818377 PMC5846149

443. Wang D Activation of PPARγ inhibits pro-inflammatory cytokines production by upregulation of miR-124 in vitro and in vivo Biochem Biophys. Res Commun. 2017 486 726 731 28342874 10.1016/j.bbrc.2017.03.106 Wang, D. et al. Activation of PPARγ inhibits pro-inflammatory cytokines production by upregulation of miR-124 in vitro and in vivo. Biochem Biophys. Res Commun. 486 , 726–731 (2017). 28342874 10.1016/j.bbrc.2017.03.106

444. Ferreira AE PPAR-γ/IL-10 axis inhibits MyD88 expression and ameliorates murine polymicrobial sepsis J. Immunol. 2014 192 2357 2365 24489087 10.4049/jimmunol.1302375 PMC3943997 Ferreira, A. E. et al. PPAR-γ/IL-10 axis inhibits MyD88 expression and ameliorates murine polymicrobial sepsis. J. Immunol. 192 , 2357–2365 (2014). 24489087 10.4049/jimmunol.1302375 PMC3943997

445. Wang C Zhou G Zeng Z Effects of peroxisome proliferator-activated receptor-β/δ on sepsis induced acute lung injury Chin. Med. J. (Engl.). 2014 127 2129 2137 24890166 Wang, C., Zhou, G. & Zeng, Z. Effects of peroxisome proliferator-activated receptor-β/δ on sepsis induced acute lung injury. Chin. Med. J. (Engl.). 127 , 2129–2137 (2014). 24890166

446. Kim, I. S., Silwal, P. & Jo, E. K. Peroxisome proliferator-activated receptor-targeted therapies: Challenges upon infectious diseases. Cells . 12 , (2023). 10.3390/cells12040650 PMC9954612 36831317

447. Leon Rodriguez DA Carmona FD González CI Martin J Evaluation of VDR gene polymorphisms in Trypanosoma cruzi infection and chronic Chagasic cardiomyopathy Sci. Rep. 2016 6 31263 27502545 10.1038/srep31263 PMC4977507 Leon Rodriguez, D. A., Carmona, F. D., González, C. I. & Martin, J. Evaluation of VDR gene polymorphisms in Trypanosoma cruzi infection and chronic Chagasic cardiomyopathy. Sci. Rep. 6 , 31263 (2016). 27502545 10.1038/srep31263 PMC4977507

448. Mubaraki MA Vitamin D receptor regulates intestinal inflammatory response in mice infected with blood stage malaria Microb. Pathog. 2018 117 299 303 29496525 10.1016/j.micpath.2018.02.048 Mubaraki, M. A. et al. Vitamin D receptor regulates intestinal inflammatory response in mice infected with blood stage malaria. Microb. Pathog. 117 , 299–303 (2018). 29496525 10.1016/j.micpath.2018.02.048

449. Wang Z Schaffer NE Kliewer SA Mangelsdorf DJ Nuclear receptors: emerging drug targets for parasitic diseases J. Clin. Invest. 2017 127 1165 1171 28165341 10.1172/JCI88890 PMC5373876 Wang, Z., Schaffer, N. E., Kliewer, S. A. & Mangelsdorf, D. J. Nuclear receptors: emerging drug targets for parasitic diseases. J. Clin. Invest. 127 , 1165–1171 (2017). 28165341 10.1172/JCI88890 PMC5373876

450. Wang Z The nuclear receptor DAF-12 regulates nutrient metabolism and reproductive growth in nematodes PLoS Genet 2015 11 e1005027 25774872 10.1371/journal.pgen.1005027 PMC4361679 Wang, Z. et al. The nuclear receptor DAF-12 regulates nutrient metabolism and reproductive growth in nematodes. PLoS Genet 11 , e1005027 (2015). 25774872 10.1371/journal.pgen.1005027 PMC4361679

451. Albarqi MM Regulation of life cycle checkpoints and developmental activation of infective larvae in strongyloides stercoralis by dafachronic acid PLoS Pathog. 2016 12 e1005358 26727267 10.1371/journal.ppat.1005358 PMC4703199 Albarqi, M. M. et al. Regulation of life cycle checkpoints and developmental activation of infective larvae in strongyloides stercoralis by dafachronic acid. PLoS Pathog. 12 , e1005358 (2016). 26727267 10.1371/journal.ppat.1005358 PMC4703199

452. Wang, Z. et al. Characterization of the endogenous DAF-12 ligand and its use as an anthelmintic agent in Strongyloides stercoralis. Elife . 10 , (2021). 10.7554/eLife.73535 PMC8651287 34874004

453. Cheong, M. C. et al. Identification of a nuclear receptor/coactivator developmental signaling pathway in the nematode parasite Strongyloides stercoralis. Proc Natl Acad Sci USA . 118 , (2021). 10.1073/pnas.2021864118 PMC7923533 33602820

454. Joham AE Polycystic ovary syndrome Lancet Diab. Endocrinol. 2022 10 668 680 10.1016/S2213-8587(22)00163-2 35934017 Joham, A. E. et al. Polycystic ovary syndrome. Lancet Diab. Endocrinol. 10 , 668–680 (2022). 10.1016/S2213-8587(22)00163-2 35934017

455. Livadas S Prevalence and impact of hyperandrogenemia in 1,218 women with polycystic ovary syndrome Endocrine 2014 47 631 638 24752393 10.1007/s12020-014-0200-7 Livadas, S. et al. Prevalence and impact of hyperandrogenemia in 1,218 women with polycystic ovary syndrome. Endocrine 47 , 631–638 (2014). 24752393 10.1007/s12020-014-0200-7

456. Yun C The microbial metabolite agmatine acts as an FXR agonist to promote polycystic ovary syndrome in female mice Nat. Metab. 2024 6 947 962 38769396 10.1038/s42255-024-01041-8 Yun, C. et al. The microbial metabolite agmatine acts as an FXR agonist to promote polycystic ovary syndrome in female mice. Nat. Metab. 6 , 947–962 (2024). 38769396 10.1038/s42255-024-01041-8

457. Przybycień, P., Gąsior-Perczak, D. & Placha, W. Cannabinoids and PPAR ligands: The future in treatment of polycystic ovary syndrome women with obesity and reduced fertility. Cells . 11 , (2022). 10.3390/cells11162569 PMC9406585 36010645

458. Lan H Sinapic acid modulates oxidative stress and metabolic disturbances to attenuate ovarian fibrosis in letrozole-induced polycystic ovary syndrome SD rats Food Sci. Nutr. 2024 12 2917 2931 38628198 10.1002/fsn3.3973 PMC11016395 Lan, H. et al. Sinapic acid modulates oxidative stress and metabolic disturbances to attenuate ovarian fibrosis in letrozole-induced polycystic ovary syndrome SD rats. Food Sci. Nutr. 12 , 2917–2931 (2024). 38628198 10.1002/fsn3.3973 PMC11016395

459. Liu Y PPAR-α inhibits DHEA-induced ferroptosis in granulosa cells through upregulation of FADS2 Biochem Biophys. Res Commun. 2024 715 150005 38678785 10.1016/j.bbrc.2024.150005 Liu, Y. et al. PPAR-α inhibits DHEA-induced ferroptosis in granulosa cells through upregulation of FADS2. Biochem Biophys. Res Commun. 715 , 150005 (2024). 38678785 10.1016/j.bbrc.2024.150005

460. Borahay MA Estrogen receptors and signaling in fibroids: Role in pathobiology and therapeutic implications Reprod. Sci. 2017 24 1235 1244 27872195 10.1177/1933719116678686 PMC6344829 Borahay, M. A. et al. Estrogen receptors and signaling in fibroids: Role in pathobiology and therapeutic implications. Reprod. Sci. 24 , 1235–1244 (2017). 27872195 10.1177/1933719116678686 PMC6344829

461. Yin H Expression profiling of nuclear receptors identifies key roles of NR4A subfamily in uterine fibroids Mol. Endocrinol. 2013 27 726 740 23550059 10.1210/me.2012-1305 PMC3634117 Yin, H. et al. Expression profiling of nuclear receptors identifies key roles of NR4A subfamily in uterine fibroids. Mol. Endocrinol. 27 , 726–740 (2013). 23550059 10.1210/me.2012-1305 PMC3634117

462. Chung KW Impairment of PPARα and the fatty acid oxidation pathway aggravates renal fibrosis during aging J. Am. Soc. Nephrol. 2018 29 1223 1237 29440279 10.1681/ASN.2017070802 PMC5875952 Chung, K. W. et al. Impairment of PPARα and the fatty acid oxidation pathway aggravates renal fibrosis during aging. J. Am. Soc. Nephrol. 29 , 1223–1237 (2018). 29440279 10.1681/ASN.2017070802 PMC5875952

463. Jao TM ATF6α downregulation of PPARα promotes lipotoxicity-induced tubulointerstitial fibrosis Kidney Int 2019 95 577 589 30639234 10.1016/j.kint.2018.09.023 Jao, T. M. et al. ATF6α downregulation of PPARα promotes lipotoxicity-induced tubulointerstitial fibrosis. Kidney Int 95 , 577–589 (2019). 30639234 10.1016/j.kint.2018.09.023

464. Kirkby NS Cyclooxygenase-2 selectively controls renal blood flow through a novel PPARβ/δ-dependent vasodilator pathway Hypertension 2018 71 297 305 29295852 10.1161/HYPERTENSIONAHA.117.09906 PMC5770101 Kirkby, N. S. et al. Cyclooxygenase-2 selectively controls renal blood flow through a novel PPARβ/δ-dependent vasodilator pathway. Hypertension 71 , 297–305 (2018). 29295852 10.1161/HYPERTENSIONAHA.117.09906 PMC5770101

465. Romero M Activation of peroxisome proliferator activator receptor β/δ improves endothelial dysfunction and protects kidney in murine lupus Hypertension 2017 69 641 650 28242713 10.1161/HYPERTENSIONAHA.116.08655 Romero, M. et al. Activation of peroxisome proliferator activator receptor β/δ improves endothelial dysfunction and protects kidney in murine lupus. Hypertension 69 , 641–650 (2017). 28242713 10.1161/HYPERTENSIONAHA.116.08655

466. Lee G PGC-1α, a potential therapeutic target against kidney aging Aging Cell 2019 18 e12994 31313501 10.1111/acel.12994 PMC6718532 Lee, G. et al. PGC-1α, a potential therapeutic target against kidney aging. Aging Cell 18 , e12994 (2019). 31313501 10.1111/acel.12994 PMC6718532

467. Zhao J Genomic integration of ERRγ-HNF1β regulates renal bioenergetics and prevents chronic kidney disease Proc. Natl. Acad. Sci. USA 2018 115 E4910 e4919 29735694 10.1073/pnas.1804965115 PMC6003475 Zhao, J. et al. Genomic integration of ERRγ-HNF1β regulates renal bioenergetics and prevents chronic kidney disease. Proc. Natl. Acad. Sci. USA 115 , E4910–e4919 (2018). 29735694 10.1073/pnas.1804965115 PMC6003475

468. Tsushida K Estrogen-related receptor α is essential for maintaining mitochondrial integrity in cisplatin-induced acute kidney injury Biochem Biophys. Res Commun. 2018 498 918 924 29545177 10.1016/j.bbrc.2018.03.080 Tsushida, K. et al. Estrogen-related receptor α is essential for maintaining mitochondrial integrity in cisplatin-induced acute kidney injury. Biochem Biophys. Res Commun. 498 , 918–924 (2018). 29545177 10.1016/j.bbrc.2018.03.080

469. Li A LC3 promotes the nuclear translocation of the vitamin D receptor and decreases fibrogenic gene expression in proximal renal tubules Metabolism 2019 98 95 103 31226352 10.1016/j.metabol.2019.06.008 Li, A. et al. LC3 promotes the nuclear translocation of the vitamin D receptor and decreases fibrogenic gene expression in proximal renal tubules. Metabolism 98 , 95–103 (2019). 31226352 10.1016/j.metabol.2019.06.008

470. Wang XX A dual agonist of farnesoid X receptor (FXR) and the G protein-coupled receptor TGR5, INT-767, reverses age-related kidney disease in mice J. Biol. Chem. 2017 292 12018 12024 28596381 10.1074/jbc.C117.794982 PMC5519354 Wang, X. X. et al. A dual agonist of farnesoid X receptor (FXR) and the G protein-coupled receptor TGR5, INT-767, reverses age-related kidney disease in mice. J. Biol. Chem. 292 , 12018–12024 (2017). 28596381 10.1074/jbc.C117.794982 PMC5519354

471. Doan TB Graham JD Clarke CL Emerging functional roles of nuclear receptors in breast cancer J. Mol. Endocrinol. 2017 58 R169 r190 28087820 10.1530/JME-16-0082 Doan, T. B., Graham, J. D. & Clarke, C. L. Emerging functional roles of nuclear receptors in breast cancer. J. Mol. Endocrinol. 58 , R169–r190 (2017). 28087820 10.1530/JME-16-0082

472. Xu S Nr4a1 marks a distinctive ILC2 activation subset in the mouse inflammatory lung BMC Biol. 2023 21 218 37833706 10.1186/s12915-023-01690-3 PMC10576290 Xu, S. et al. Nr4a1 marks a distinctive ILC2 activation subset in the mouse inflammatory lung. BMC Biol. 21 , 218 (2023). 37833706 10.1186/s12915-023-01690-3 PMC10576290

473. Moescheid, M. F. et al. The retinoic acid family-like nuclear receptor SmRAR identified by single-cell transcriptomics of ovarian cells controls oocyte differentiation in Schistosoma mansoni. Nucleic Acids Res. 53 , gkae1228 (2024). 10.1093/nar/gkae1228 PMC11879061 39676663

474. Li QS Zheng PS ESRRB Inhibits the TGFβ signaling pathway to drive cell proliferation in cervical cancer Cancer Res 2023 83 3095 3114 37350664 10.1158/0008-5472.CAN-23-0067 PMC10502452 Li, Q. S. & Zheng, P. S. ESRRB Inhibits the TGFβ signaling pathway to drive cell proliferation in cervical cancer. Cancer Res 83 , 3095–3114 (2023). 37350664 10.1158/0008-5472.CAN-23-0067 PMC10502452

475. Farr JN Osteoprotection through the deletion of the transcription factor Rorβ in mice J. Bone Miner. Res. 2018 33 720 731 29206307 10.1002/jbmr.3351 PMC5925424 Farr, J. N. et al. Osteoprotection through the deletion of the transcription factor Rorβ in mice. J. Bone Miner. Res. 33 , 720–731 (2018). 29206307 10.1002/jbmr.3351 PMC5925424

476. Li W Molecular basis of nucleosomal H3K36 methylation by NSD methyltransferases Nature 2021 590 498 503 33361816 10.1038/s41586-020-03069-8 PMC7889650 Li, W. et al. Molecular basis of nucleosomal H3K36 methylation by NSD methyltransferases. Nature 590 , 498–503 (2021). 33361816 10.1038/s41586-020-03069-8 PMC7889650

477. Hoelzgen F Structural basis for the intracellular regulation of ferritin degradation Nat. Commun. 2024 15 3802 38714719 10.1038/s41467-024-48151-1 PMC11076521 Hoelzgen, F. et al. Structural basis for the intracellular regulation of ferritin degradation. Nat. Commun. 15 , 3802 (2024). 38714719 10.1038/s41467-024-48151-1 PMC11076521

478. Moret M Beam search for automated design and scoring of novel ROR ligands with machine intelligence* Angew. Chem. Int. Ed. Engl. 2021 60 19477 19482 34165856 10.1002/anie.202104405 PMC8457062 Moret, M. et al. Beam search for automated design and scoring of novel ROR ligands with machine intelligence*. Angew. Chem. Int. Ed. Engl. 60 , 19477–19482 (2021). 34165856 10.1002/anie.202104405 PMC8457062

479. Foo J Characterization of novel small molecule inhibitors of estrogen receptor-activation function 2 (ER-AF2) Breast Cancer Res. 2024 26 168 39593108 10.1186/s13058-024-01926-2 PMC11590367 Foo, J. et al. Characterization of novel small molecule inhibitors of estrogen receptor-activation function 2 (ER-AF2). Breast Cancer Res. 26 , 168 (2024). 39593108 10.1186/s13058-024-01926-2 PMC11590367

480. van Ertvelde J Optimization of an adverse outcome pathway network on chemical-induced cholestasis using an artificial intelligence-assisted data collection and confidence level quantification approach J. Biomed. Inf. 2023 145 104465 10.1016/j.jbi.2023.104465 37541407 van Ertvelde, J. et al. Optimization of an adverse outcome pathway network on chemical-induced cholestasis using an artificial intelligence-assisted data collection and confidence level quantification approach. J. Biomed. Inf. 145 , 104465 (2023). 10.1016/j.jbi.2023.104465 37541407

481. Bhimsaria D Hidden modes of DNA binding by human nuclear receptors Nat. Commun. 2023 14 4179 37443151 10.1038/s41467-023-39577-0 PMC10345098 Bhimsaria, D. et al. Hidden modes of DNA binding by human nuclear receptors. Nat. Commun. 14 , 4179 (2023). 37443151 10.1038/s41467-023-39577-0 PMC10345098

482. Ryan, C. et al. Nobiletin stimulates adrenal hormones and modulates the circadian clock in mice. Nutrients . 16 , (2024). 10.3390/nu16101491 PMC11123956 38794729

483. Parent EE Fowler AM Nuclear receptor imaging in vivo-clinical and research advances J. Endocr. Soc. 2023 7 bvac197 36655003 10.1210/jendso/bvac197 PMC9838808 Parent, E. E. & Fowler, A. M. Nuclear receptor imaging in vivo-clinical and research advances. J. Endocr. Soc. 7 , bvac197 (2023). 36655003 10.1210/jendso/bvac197 PMC9838808

484. Dart DA Bevan CL In vivo imaging of nuclear receptor transcriptional activity Methods Mol. Biol. 2016 1443 203 217 27246342 10.1007/978-1-4939-3724-0_13 Dart, D. A. & Bevan, C. L. In vivo imaging of nuclear receptor transcriptional activity. Methods Mol. Biol. 1443 , 203–217 (2016). 27246342 10.1007/978-1-4939-3724-0_13

485. Guan XJ Zhang YY Zheng X Hao HP Drug discovery inspired from nuclear receptor sensing of microbial signals Trends Mol. Med. 2021 27 624 626 33865719 10.1016/j.molmed.2021.03.007 Guan, X. J., Zhang, Y. Y., Zheng, X. & Hao, H. P. Drug discovery inspired from nuclear receptor sensing of microbial signals. Trends Mol. Med. 27 , 624–626 (2021). 33865719 10.1016/j.molmed.2021.03.007

486. Dvořák Z Targeting the pregnane X receptor using microbial metabolite mimicry EMBO Mol. Med. 2020 12 e11621 32153125 10.15252/emmm.201911621 PMC7136958 Dvořák, Z. et al. Targeting the pregnane X receptor using microbial metabolite mimicry. EMBO Mol. Med. 12 , e11621 (2020). 32153125 10.15252/emmm.201911621 PMC7136958

487. Dvořák Z Sokol H Mani S Drug mimicry: Promiscuous receptors PXR and AhR, and microbial metabolite interactions in the intestine Trends Pharmacol. Sci. 2020 41 900 908 33097284 10.1016/j.tips.2020.09.013 PMC7669654 Dvořák, Z., Sokol, H. & Mani, S. Drug mimicry: Promiscuous receptors PXR and AhR, and microbial metabolite interactions in the intestine. Trends Pharmacol. Sci. 41 , 900–908 (2020). 33097284 10.1016/j.tips.2020.09.013 PMC7669654

488. Sun L Gut microbiota and intestinal FXR mediate the clinical benefits of metformin Nat. Med. 2018 24 1919 1929 30397356 10.1038/s41591-018-0222-4 PMC6479226 Sun, L. et al. Gut microbiota and intestinal FXR mediate the clinical benefits of metformin. Nat. Med. 24 , 1919–1929 (2018). 30397356 10.1038/s41591-018-0222-4 PMC6479226

489. Friedman ES FXR-dependent modulation of the human small intestinal microbiome by the bile acid derivative obeticholic acid Gastroenterology 2018 155 1741 1752.e1745 30144429 10.1053/j.gastro.2018.08.022 PMC6279623 Friedman, E. S. et al. FXR-dependent modulation of the human small intestinal microbiome by the bile acid derivative obeticholic acid. Gastroenterology 155 , 1741–1752.e1745 (2018). 30144429 10.1053/j.gastro.2018.08.022 PMC6279623

490. Pathak P Intestine farnesoid X receptor agonist and the gut microbiota activate G-protein bile acid receptor-1 signaling to improve metabolism Hepatology 2018 68 1574 1588 29486523 10.1002/hep.29857 PMC6111007 Pathak, P. et al. Intestine farnesoid X receptor agonist and the gut microbiota activate G-protein bile acid receptor-1 signaling to improve metabolism. Hepatology 68 , 1574–1588 (2018). 29486523 10.1002/hep.29857 PMC6111007

491. Pignolo RJ Palovarotene for fibrodysplasia ossificans progressiva (FOP): Results of a randomized, placebo-controlled, double-blind phase 2 trial J. Bone Miner. Res. 2022 37 1891 1902 35854638 10.1002/jbmr.4655 PMC9804935 Pignolo, R. J. et al. Palovarotene for fibrodysplasia ossificans progressiva (FOP): Results of a randomized, placebo-controlled, double-blind phase 2 trial. J. Bone Miner. Res. 37 , 1891–1902 (2022). 35854638 10.1002/jbmr.4655 PMC9804935

492. Shimono K Potent inhibition of heterotopic ossification by nuclear retinoic acid receptor-γ agonists Nat. Med. 2011 17 454 460 21460849 10.1038/nm.2334 PMC3073031 Shimono, K. et al. Potent inhibition of heterotopic ossification by nuclear retinoic acid receptor-γ agonists. Nat. Med. 17 , 454–460 (2011). 21460849 10.1038/nm.2334 PMC3073031

493. Kowdley KV A randomized, placebo-controlled, phase II study of obeticholic acid for primary sclerosing cholangitis J. Hepatol. 2020 73 94 101 32165251 10.1016/j.jhep.2020.02.033 PMC8157171 Kowdley, K. V. et al. A randomized, placebo-controlled, phase II study of obeticholic acid for primary sclerosing cholangitis. J. Hepatol. 73 , 94–101 (2020). 32165251 10.1016/j.jhep.2020.02.033 PMC8157171

494. Camilleri M Randomised clinical trial: Significant biochemical and colonic transit effects of the farnesoid X receptor agonist tropifexor in patients with primary bile acid diarrhoea Aliment. Pharmacol. Ther. 2020 52 808 820 32702169 10.1111/apt.15967 Camilleri, M. et al. Randomised clinical trial: Significant biochemical and colonic transit effects of the farnesoid X receptor agonist tropifexor in patients with primary bile acid diarrhoea. Aliment. Pharmacol. Ther. 52 , 808–820 (2020). 32702169 10.1111/apt.15967

495. Mudaliar S Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease Gastroenterology 2013 145 574 582.e571 23727264 10.1053/j.gastro.2013.05.042 Mudaliar, S. et al. Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology 145 , 574–582.e571 (2013). 23727264 10.1053/j.gastro.2013.05.042

496. Bullock TA Significant improvement of facial actinic keratoses after blue light photodynamic therapy with oral vitamin D pretreatment: An interventional cohort-controlled trial J. Am. Acad. Dermatol. 2022 87 80 86 35314199 10.1016/j.jaad.2022.02.067 PMC9233022 Bullock, T. A. et al. Significant improvement of facial actinic keratoses after blue light photodynamic therapy with oral vitamin D pretreatment: An interventional cohort-controlled trial. J. Am. Acad. Dermatol. 87 , 80–86 (2022). 35314199 10.1016/j.jaad.2022.02.067 PMC9233022

497. Kumar S Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma Blood 2012 119 4375 4382 22422823 10.1182/blood-2011-11-395749 Kumar, S. et al. Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood 119 , 4375–4382 (2012). 22422823 10.1182/blood-2011-11-395749

498. Schroten NF Short-term vitamin D3 supplementation lowers plasma renin activity in patients with stable chronic heart failure: an open-label, blinded end point, randomized prospective trial (VitD-CHF trial) Am. Heart J. 2013 166 357 364.e352 23895820 10.1016/j.ahj.2013.05.009 Schroten, N. F. et al. Short-term vitamin D3 supplementation lowers plasma renin activity in patients with stable chronic heart failure: an open-label, blinded end point, randomized prospective trial (VitD-CHF trial). Am. Heart J. 166 , 357–364.e352 (2013). 23895820 10.1016/j.ahj.2013.05.009

499. Alshahawey M The impact of cholecalciferol on markers of vascular calcification in hemodialysis patients: A randomized placebo controlled study Nutr. Metab. Cardiovasc. Dis. 2021 31 626 633 33594986 10.1016/j.numecd.2020.09.014 Alshahawey, M. et al. The impact of cholecalciferol on markers of vascular calcification in hemodialysis patients: A randomized placebo controlled study. Nutr. Metab. Cardiovasc. Dis. 31 , 626–633 (2021). 33594986 10.1016/j.numecd.2020.09.014

500. Mily A Significant effects of oral phenylbutyrate and vitamin D3 adjunctive therapy in pulmonary tuberculosis: A randomized controlled trial PLoS One 2015 10 e0138340 26394045 10.1371/journal.pone.0138340 PMC4578887 Mily, A. et al. Significant effects of oral phenylbutyrate and vitamin D3 adjunctive therapy in pulmonary tuberculosis: A randomized controlled trial. PLoS One 10 , e0138340 (2015). 26394045 10.1371/journal.pone.0138340 PMC4578887

501. Ceglia L Effect of vitamin D(3) vs. calcifediol on VDR concentration and fiber size in skeletal muscle J. Bone Miner. Metab. 2023 41 41 51 36385193 10.1007/s00774-022-01374-y Ceglia, L. et al. Effect of vitamin D(3) vs. calcifediol on VDR concentration and fiber size in skeletal muscle. J. Bone Miner. Metab. 41 , 41–51 (2023). 36385193 10.1007/s00774-022-01374-y

502. Borzutzky A Effect of weekly vitamin D supplementation on the severity of atopic dermatitis and type 2 immunity biomarkers in children: A randomized controlled trial J. Eur. Acad. Dermatol. Venereol. 2024 38 1760 1768 38483248 10.1111/jdv.19959 Borzutzky, A. et al. Effect of weekly vitamin D supplementation on the severity of atopic dermatitis and type 2 immunity biomarkers in children: A randomized controlled trial. J. Eur. Acad. Dermatol. Venereol. 38 , 1760–1768 (2024). 38483248 10.1111/jdv.19959

503. Holt R Low serum anti-Müllerian hormone is associated with semen quality in infertile men and not influenced by vitamin D supplementation BMC Med 2023 21 79 36855109 10.1186/s12916-023-02782-1 PMC9976369 Holt, R. et al. Low serum anti-Müllerian hormone is associated with semen quality in infertile men and not influenced by vitamin D supplementation. BMC Med 21 , 79 (2023). 36855109 10.1186/s12916-023-02782-1 PMC9976369

504. Lundwall K Jörneskog G Jacobson SH Spaak J Paricalcitol, microvascular and endothelial function in non-diabetic chronic kidney disease: A randomized trial Am. J. Nephrol. 2015 42 265 273 26496210 10.1159/000441364 Lundwall, K., Jörneskog, G., Jacobson, S. H. & Spaak, J. Paricalcitol, microvascular and endothelial function in non-diabetic chronic kidney disease: A randomized trial. Am. J. Nephrol. 42 , 265–273 (2015). 26496210 10.1159/000441364

505. Ganmaa D Vitamin D supplements for prevention of tuberculosis infection and disease N. Engl. J. Med. 2020 383 359 368 32706534 10.1056/NEJMoa1915176 PMC7476371 Ganmaa, D. et al. Vitamin D supplements for prevention of tuberculosis infection and disease. N. Engl. J. Med. 383 , 359–368 (2020). 32706534 10.1056/NEJMoa1915176 PMC7476371

506. Oblak M Paricalcitol versus placebo for reduction of proteinuria in kidney transplant recipients: a double-blind, randomized controlled trial Transpl. Int. 2018 31 1391 1404 30062716 10.1111/tri.13323 Oblak, M. et al. Paricalcitol versus placebo for reduction of proteinuria in kidney transplant recipients: a double-blind, randomized controlled trial. Transpl. Int. 31 , 1391–1404 (2018). 30062716 10.1111/tri.13323

507. Wang AY Effect of paricalcitol on left ventricular mass and function in CKD-the OPERA trial J. Am. Soc. Nephrol. 2014 25 175 186 24052631 10.1681/ASN.2013010103 PMC3871774 Wang, A. Y. et al. Effect of paricalcitol on left ventricular mass and function in CKD-the OPERA trial. J. Am. Soc. Nephrol. 25 , 175–186 (2014). 24052631 10.1681/ASN.2013010103 PMC3871774

508. Parvanova A Moderate salt restriction with or without paricalcitol in type 2 diabetes and losartan-resistant macroalbuminuria (PROCEED): a randomised, double-blind, placebo-controlled, crossover trial Lancet Diab. Endocrinol. 2018 6 27 40 10.1016/S2213-8587(17)30359-5 29104158 Parvanova, A. et al. Moderate salt restriction with or without paricalcitol in type 2 diabetes and losartan-resistant macroalbuminuria (PROCEED): a randomised, double-blind, placebo-controlled, crossover trial. Lancet Diab. Endocrinol. 6 , 27–40 (2018). 10.1016/S2213-8587(17)30359-5 29104158

509. de Zeeuw D Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes (VITAL study): a randomised controlled trial Lancet 2010 376 1543 1551 21055801 10.1016/S0140-6736(10)61032-X de Zeeuw, D. et al. Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes (VITAL study): a randomised controlled trial. Lancet 376 , 1543–1551 (2010). 21055801 10.1016/S0140-6736(10)61032-X

510. Ussif A Paricalcitol supplementation during the first year after kidney transplantation does not affect calcification propensity score BMC Nephrol. 2018 19 212 30134956 10.1186/s12882-018-1000-8 PMC6106758 Ussif, A. et al. Paricalcitol supplementation during the first year after kidney transplantation does not affect calcification propensity score. BMC Nephrol. 19 , 212 (2018). 30134956 10.1186/s12882-018-1000-8 PMC6106758

511. Tu H Effects of calcium and vitamin D3 on transforming growth factors in rectal mucosa of sporadic colorectal adenoma patients: A randomized controlled trial Mol. Carcinog. 2015 54 270 280 24166893 10.1002/mc.22096 PMC4484733 Tu, H. et al. Effects of calcium and vitamin D3 on transforming growth factors in rectal mucosa of sporadic colorectal adenoma patients: A randomized controlled trial. Mol. Carcinog. 54 , 270–280 (2015). 24166893 10.1002/mc.22096 PMC4484733

512. Rorie A Goldner WS Lyden E Poole JA Beneficial role for supplemental vitamin D3 treatment in chronic urticaria: a randomized study Ann. Allergy Asthma Immunol. 2014 112 376 382 24507460 10.1016/j.anai.2014.01.010 Rorie, A., Goldner, W. S., Lyden, E. & Poole, J. A. Beneficial role for supplemental vitamin D3 treatment in chronic urticaria: a randomized study. Ann. Allergy Asthma Immunol. 112 , 376–382 (2014). 24507460 10.1016/j.anai.2014.01.010

513. Meireles MS Effect of cholecalciferol on vitamin D-regulatory proteins in monocytes and on inflammatory markers in dialysis patients: A randomized controlled trial Clin. Nutr. 2016 35 1251 1258 27161894 10.1016/j.clnu.2016.04.014 Meireles, M. S. et al. Effect of cholecalciferol on vitamin D-regulatory proteins in monocytes and on inflammatory markers in dialysis patients: A randomized controlled trial. Clin. Nutr. 35 , 1251–1258 (2016). 27161894 10.1016/j.clnu.2016.04.014

514. Mendes MM Vitamin D supplementation and sunlight exposure on serum vitamin D concentrations in 2 parallel, double-blind, randomized, placebo-controlled trials J. Nutr. 2021 151 3137 3150 34255034 10.1093/jn/nxab209 Mendes, M. M. et al. Vitamin D supplementation and sunlight exposure on serum vitamin D concentrations in 2 parallel, double-blind, randomized, placebo-controlled trials. J. Nutr. 151 , 3137–3150 (2021). 34255034 10.1093/jn/nxab209

515. Noskova P Neonatal effect of remifentanil in general anaesthesia for caesarean section: a randomized trial BMC Anesthesiol. 2015 15 38 25821405 10.1186/s12871-015-0020-1 PMC4377196 Noskova, P. et al. Neonatal effect of remifentanil in general anaesthesia for caesarean section: a randomized trial. BMC Anesthesiol. 15 , 38 (2015). 25821405 10.1186/s12871-015-0020-1 PMC4377196

516. Mueller M Ursodeoxycholic acid: Effects on hepatic unfolded protein response, apoptosis and oxidative stress in morbidly obese patients Liver Int 2018 38 523 531 28853202 10.1111/liv.13562 PMC5836915 Mueller, M. et al. Ursodeoxycholic acid: Effects on hepatic unfolded protein response, apoptosis and oxidative stress in morbidly obese patients. Liver Int 38 , 523–531 (2018). 28853202 10.1111/liv.13562 PMC5836915

517. Debono M Mifepristone reduces insulin resistance in patient volunteers with adrenal incidentalomas that secrete low levels of cortisol: a pilot study PLoS One 2013 8 e60984 23577182 10.1371/journal.pone.0060984 PMC3618218 Debono, M. et al. Mifepristone reduces insulin resistance in patient volunteers with adrenal incidentalomas that secrete low levels of cortisol: a pilot study. PLoS One 8 , e60984 (2013). 23577182 10.1371/journal.pone.0060984 PMC3618218

518. Pivonello R Glucocorticoid receptor antagonism upregulates somatostatin receptor subtype 2 expression in ACTH-producing neuroendocrine tumors: New insight based on the selective glucocorticoid receptor modulator relacorilant Front. Endocrinol. (Lausanne) 2021 12 793262 35058882 10.3389/fendo.2021.793262 PMC8764187 Pivonello, R. et al. Glucocorticoid receptor antagonism upregulates somatostatin receptor subtype 2 expression in ACTH-producing neuroendocrine tumors: New insight based on the selective glucocorticoid receptor modulator relacorilant. Front. Endocrinol. (Lausanne) 12 , 793262 (2021). 35058882 10.3389/fendo.2021.793262 PMC8764187

519. Golier JA A randomized, double-blind, placebo-controlled, crossover trial of mifepristone in Gulf War veterans with chronic multisymptom illness Psychoneuroendocrinology 2016 64 22 30 26600007 10.1016/j.psyneuen.2015.11.001 Golier, J. A. et al. A randomized, double-blind, placebo-controlled, crossover trial of mifepristone in Gulf War veterans with chronic multisymptom illness. Psychoneuroendocrinology 64 , 22–30 (2016). 26600007 10.1016/j.psyneuen.2015.11.001

520. Serritella AV Phase I/II trial of enzalutamide and mifepristone, a glucocorticoid receptor antagonist, for metastatic castration-resistant prostate cancer Clin. Cancer Res. 2022 28 1549 1559 35110415 10.1158/1078-0432.CCR-21-4049 PMC9012680 Serritella, A. V. et al. Phase I/II trial of enzalutamide and mifepristone, a glucocorticoid receptor antagonist, for metastatic castration-resistant prostate cancer. Clin. Cancer Res. 28 , 1549–1559 (2022). 35110415 10.1158/1078-0432.CCR-21-4049 PMC9012680