Роль ядерных рецепторов в развитии множественного склероза: обзор.

Introduction

MS, a neurological disease of the central nervous system, is prevalent in two million people worldwide. It was introduced by Jean-Martin Charcot in 1886 and its clinical and pathological features have been explained (Kumar et al. 2011 ). MS is an autoimmune disorder characterized by CNS inflammation and demyelination. Its pathogenesis is not clear yet, and studies have revealed that both genetic and environmental factors lead to its progression (Chen et al. 2019 ). The pathogenesis of MS involves two intertwined processes: inflammatory demyelination and progressive neurodegeneration. Both approaches are pivotal to disease onset. At the onset of the disease, the infiltration of circulating monocyte-derived macrophages indicates that inflammation is predominant in the early stages. Subsequently, a gradual transition occurs, which leads to demyelination and neurodegeneration. Despite profound achievements in MS medication, the potential mechanisms for reversing disease progression remain unclear (Sharma et al. 2022 ; Willems et al. 2021 ). While advancements in pharmacological treatments have provided symptomatic relief and slowed disease progression in multiple sclerosis (MS), there remains a critical need to develop therapies that target the underlying molecular mechanisms driving the disease. One promising avenue is the modulation of nuclear receptors (NRs), which play pivotal roles in regulating inflammation, lipid metabolism, and cellular homeostasis—processes that are profoundly dysregulated in MS. Among these NRs, liver X receptors (LXRs) and retinoid X receptors (RXRs) have emerged as key regulators of cholesterol metabolism and immune responses. LXRs, activated by oxysterols, promote cholesterol efflux and reduce inflammatory gene expression, while RXRs serve as obligate heterodimerization partners for LXRs and other NRs, amplifying their regulatory effects (Fellows Maxwell et al. 2019 ). The stimulation of these receptors has been shown to modulate microglial activation, astrocyte function, and endothelial cell integrity, all of which are implicated in MS pathogenesis (Lan et al. 2024 ). For instance, RXR agonists have been demonstrated to enhance the expression of ATP-binding cassette transporter A1 (ABCA1), a critical mediator of cholesterol efflux, in cultured endothelial cells, thereby reducing lipid accumulation and inflammation in vessel walls. By exploring the therapeutic potential of NRs, this review aims to bridge the gap between current MS treatments and emerging strategies that address both the inflammatory and degenerative components of the disease. Understanding the intricate interplay between NR signaling pathways and MS pathophysiology could pave the way for novel, multi-targeted therapies that not only alleviate symptoms but also halt or reverse disease progression.

After stimulating nuclear receptors by cytokines, peptides, and growth factors, they bind to the nuclear receptor (NR) to DNA to control cell growth and differentiation, and the metabolism of proteins produced by cell receptors changes (Almeida and Conda-Sheridan 2019 ). Nuclear receptors comprise a family of 48 members. These proteins serve as ligand sensors, transcription factors, and controllers of gene expression (Willems et al. 2021 ). Each NR has a common structural pattern, with an activation factor (AF-1) in the N-terminal domain (NTD), DNA-binding domain (DBD) in the middle, flexible hinge region, and activation factor 2 (AF-2) in the C-terminal ligand-binding domain (LBD) (Königshofer et al. 2021 ). NRs can be categorized into four groups based on their DNA-binding capacity and mechanism of action: Type 1 receptors are illustrated by steroid receptors and are homodimeric. They bind to DNA sequences, such as inverted repeats specific to hormones, including androgen (AR), estrogen (ER), progesterone (PR), and glucocorticoid (GR). Type 2 receptors, also known as nonsteroidal receptors, are primarily located in the nucleus. There are groups of these proteins that work together, such as retinoid X receptor (RXR) and coreceptor proteins, such as retinoic acid receptor (RAR), vitamin D receptor (VDR), thyroid hormone receptor (TR), nerve growth factor-induced gene B (NGFIB), and peroxisome proliferator-activated receptors (PPAR). This heterodimeric structure binds to specific DNA repeats and remains in the nucleus (Xie, et al. 2019 ). Type 3 receptors are homodimeric NRs that pair with identical NRs and bind to particular DNA repeats. Type 4 receptors directly bind to DNA as monomers or dimers, recognizing half-site hormone-response elements within the DNA sequence. The liver X receptor (LXR) and the retinoid X receptor (RXR) are both parts of the NR family as they do not belong to any of the receptor groups such as small heterodimer partner (SHP), testicular receptor 2 and 4 (TR2 and 4), photoreceptor-specific NR (PNR), and estrogen-related receptor (ERR). They are termed ‘orphan receptors’ because their specific ligands have not been identified. Furthermore, their specific ligands have not been identified (Almeida and Conda-Sheridan 2019 ). LXR is notably abundant in the adult brain, where it acts as an intrinsic sensor for intracellular cholesterol levels and plays an essential role in regulating cholesterol homeostasis. LXR and RXR can join together to form heterodimer complexes. This facilitates reverse cholesterol transport, which happens when extra cholesterol or cholesterol precursors, such as oxysterols, are taken out of the body. This mechanism helps maintain proper cholesterol balance in the body (Alnaaim 2023 ; Wang et al. 2023 ; Huang, et al. 2021 ). Thus, LXR plays a pivotal role in cholesterol metabolism and phospholipid homeostasis and is recognized as an anti-inflammatory regulator (He et al. 2020 ). It is also acknowledged for its anti-inflammatory properties by reducing the production of pro-inflammatory cytokines, LXR agonists have been shown to protect neurons from damage caused by neuroinflammation and neurodegenerative diseases in vitro and in vivo models (Sacchetti et al. 2009 ). Furthermore, LXR knockout mice exhibit neurodegeneration, which is attributed to cholesterol-induced synaptic impairment and neuronal loss (Yang et al. 2021 ). Cholesterol metabolism plays a fundamental role in maintaining central nervous system (CNS) homeostasis, particularly in the context of myelin stability and neuronal function. In MS, dysregulation of cholesterol synthesis, transport, and efflux contributes to demyelination, neuroinflammation, and neurodegeneration. Myelin, the lipid-rich sheath surrounding axons, relies heavily on cholesterol for its structural integrity and efficient signal transmission. However, excessive cholesterol accumulation or impaired efflux can lead to toxic effects, including oxidative stress and inflammation, which exacerbate MS pathology. Oxysterols, oxidized derivatives of cholesterol, serve as natural ligands for LXRs and act as critical signaling molecules in the brain. For example, 24(S)-hydroxycholesterol (24-OHC), the most prevalent oxysterol in the brain, facilitates cholesterol turnover and has been implicated in both neuroprotective and neurotoxic processes. Notably, alterations in 24-OHC plasma levels have been observed in patients with neurodegenerative diseases, including MS, suggesting its potential as a biomarker and therapeutic target. Furthermore, neuroinflammation, a hallmark of MS, involves the activation of resident immune cells such as microglia and astrocytes, leading to the production of pro-inflammatory cytokines, reactive oxygen species (ROS), and matrix metalloproteinases (MMPs). While neuroinflammation and neurodegeneration are distinct processes, they are interconnected in MS, with chronic inflammation contributing to neuronal damage and disease progression. Thus, targeting cholesterol metabolism and neuroinflammatory pathways through NR modulation offers a dual-pronged approach to managing MS. This review will explore the roles of LXRs and RXRs in regulating these pathways and their potential as therapeutic targets for mitigating disease severity. Given the critical role of cholesterol metabolism in MS and the involvement of nuclear receptors in modulating lipid homeostasis, this review explores RXR and LXR functions in MS pathogenesis, highlighting their potential as therapeutic targets.

Cholesterol Homeostasis in MS

The brain contains 20% whole-body cholesterol and bile acids. CYP7 A1, the rate-limiting enzyme in bile acid synthesis, is expressed in the CNS (Bhargava et al. 2020 ). Cholesterol (C27H46O) is a sterol that is crucial for immune regulation and signaling and is the main component of myelin and the cell membrane in addition to being the precursor of steroid hormones and vitamin D (Lorincz et al. 2022 ). In blood circulation, cholesterol is transported by various lipoprotein particles that cannot cross the BBB (Gao and Li 2023 ). Thus, astrocytes synthesize most of the cholesterol in the brain from glucose, glutamine, or acetate derived from acetyl COA. In addition, it receives cholesterol from HDL-containing ApoE to promote regeneration of the peripheral nervous system (Villa et al. 2016 ). ApoE combines with apo A1 and LDLR to facilitate lipid transfer (Boyles et al. 1989 ). It has three major isotypes, apoE2 (cys 112, cys 158), apoE3 (cys 112, arg 158), and apoE4 (arg 112, arg 158) (Zhang et al. 2021 ). At high cholesterol levels, LXR and RXR heterodimers in astrocytes together help make cholesterol transport proteins. Therefore, ATP-binding cassette transporter A1 (ABCA1), a key regulator of cholesterol efflux, facilitates the transfer of cholesterol to ApoE-containing lipoproteins, thereby improving cholesterol clearance in MS (Borràs, et al. 2022 ). Additionally, studies have demonstrated that ApoE levels increase in microglia in aging or disease conditions, potentially altering cholesterol homeostasis in astrocytes, with the ApoE4 isoform being associated with dysregulated lipid metabolism (Tcw et al. 2022 ). ApoE isoforms are risk factors for cardiovascular, neurological, and infectious diseases. Carriers of two E4 alleles have a 9- to 15-fold higher risk of late-onset AD progression. In contrast, the E2 allele has a protective effect against Alzheimer’s. In addition, ApoE has been shown to have a higher expression level of ADP ribosylation of factor 6 (ARF6) (a protein involved in ABCA1 recycling) in the late endosome (Begcevic Brkovic, et al. 2022 ). Apo E3 is defined as neutral (Zhang et al. 2021 ).

The myelin membrane, which is made of cholesterol, is the target of immune cells, and in MS disease, neurons of the CNS are demyelinated as their primary component is cholesterol (Gao and Li 2023 ; Berghoff et al. 2021 ). After acute injury, cholesterol is recovered from myelin debris and transported to astrocytes and endothelial cells. This decline in cholesterol production improved the production of divergent oxysterols. In addition, local cholesterol synthesis is necessary for chronic trauma and demyelination. In the pathological state, myelin repair is suppressed (Berghoff et al. 2021 ). Pajoohesh Ganji et al. reported that blocked myelin requirement might be associated with the impact of myelin debris in the microenvironment on the differentiation of the OPC cell (Pajoohesh-Ganji et al. 2020 ). Berghoff et al. suggested that during the MS repair phase, microglia are required to eliminate cholesterol-rich myelin debris and change the cell environment from lower inflammation to inhibiting it so that oligodendrocyte differentiation can occur (Gao and Li 2023 ) (Fig.  1 ). Fig. 1 OPCs play a role in the maintenance of inflammation, which in turn accelerates neurodegeneration in multiple sclerosis. Impaired antigen presentation to CD4 + and CD8 + T lymphocytes can be enhanced during neuroinflammation by upregulating the MHC I and II antigen presentation molecules on OPCs, respectively, through IFNγ. The antigen-MHC I complex has the ability to trigger the production of TNFα and IFNγ by CD8 + T cells, along with the secretion of perforin and granzyme, all of which can lead to the death of specific OPC cells in the area. Through the presentation of MHC II antigens, OPCs also stimulate the proliferation and cytokine production of CD4 + memory and effector T lymphocytes. Microglia also have the ability to hinder OPC development through the production of TNFα in response to IFNγ signaling by T cells. Inhibition of OPC maturation and oligodendrocyte cell death are linked to excess extracellular IFNγ. OPC differentiation capacity can be directly diminished since IL-6 synthesis by astrocytes is stimulated by IFNγ signaling, which in turn increases OPC IL-1β expression. It is possible that IL-1β, which is produced by OPCs, directly causes neuronal cytotoxicity by improving the transmission of toxic glutamatergic synapses. In order to prevent OPC recruitment and maturation, myelin fragments from deteriorating myelin sheaths act as a repellent. All things considered, OPCs themselves maintain a neuroinflammatory state, which limits the ability of OL lineage cells to provide axonal support, repair, and remyelination (Psenicka, et al. 2021 )

OPCs play a role in the maintenance of inflammation, which in turn accelerates neurodegeneration in multiple sclerosis. Impaired antigen presentation to CD4 + and CD8 + T lymphocytes can be enhanced during neuroinflammation by upregulating the MHC I and II antigen presentation molecules on OPCs, respectively, through IFNγ. The antigen-MHC I complex has the ability to trigger the production of TNFα and IFNγ by CD8 + T cells, along with the secretion of perforin and granzyme, all of which can lead to the death of specific OPC cells in the area. Through the presentation of MHC II antigens, OPCs also stimulate the proliferation and cytokine production of CD4 + memory and effector T lymphocytes. Microglia also have the ability to hinder OPC development through the production of TNFα in response to IFNγ signaling by T cells. Inhibition of OPC maturation and oligodendrocyte cell death are linked to excess extracellular IFNγ. OPC differentiation capacity can be directly diminished since IL-6 synthesis by astrocytes is stimulated by IFNγ signaling, which in turn increases OPC IL-1β expression. It is possible that IL-1β, which is produced by OPCs, directly causes neuronal cytotoxicity by improving the transmission of toxic glutamatergic synapses. In order to prevent OPC recruitment and maturation, myelin fragments from deteriorating myelin sheaths act as a repellent. All things considered, OPCs themselves maintain a neuroinflammatory state, which limits the ability of OL lineage cells to provide axonal support, repair, and remyelination (Psenicka, et al. 2021 )

Janet K. Boyles’ research declared that the nerve is repaired at the beginning of cholesterol transport mechanism. This study suggests that Boyles et al. suggested that cholesterol transfer mechanisms play a crucial role in axon recovery and remyelination by supplying the necessary lipids for myelin repair (Boyles et al. 1989 ). CYP27 A1 also changes cholesterol into 27-hydoxycholestrol (27-OHC) in the bloodstream, while CYP46 A1 converts 24-hydroxycholestrol, which is the most oxysterol in the brain and spinal cord, and it has been proposed that the 24-OHC plasma level could be raised or diminished in patients with neurodegenerative disease in the early and late stages of the illness, respectively (Leoni and Caccia 2013 ). It has been proposed that 24-OHC plasma levels could be raised or reduced in patients with neurodegenerative disease in the early and late stages of the illness, respectively (Nury et al. 2015 ). In the case of neurodegenerative diseases, 24-OHC leaks into the cerebrospinal fluid (CSF) and hurts fat cells in the brain and spinal cord, mainly oligodendrocytes (Vejux et al. 2021 ). This changes the breakdown of cholesterol and the formation of myelin. Since 24-OHC damages fats, there would be less lanosterol, lathosterol, and desmosterol, which are cholesterol precursors. Because oligodendrocytes provide a large amount of cholesterol for the myelin sheath, when their metabolism goes wrong, it causes neurons to lose myelin, experience oxidative stress, and die. In addition, oligodendrocyte differentiation is suppressed by myelin debris and inflammatory conditions (Table  1 ). Table 1 Comprehensive table now includes an in-depth look at the mechanisms, interactions, and research directions across various aspects of cholesterol metabolism and its impact on the brain, neuroinflammation, and disease Factor Details Comparative notes Key functions Mechanisms of action Molecular interactions Impact on neuroinflammation Current research directions Cholesterol in the Brain - Brain contains 20% of body’s cholesterol, vital for immune regulation, signaling, myelin synthesis, and steroid hormone precursor - Synthesized locally in the brain due to BBB restrictions, unlike peripheral cholesterol which can be derived from diet - Maintains myelin integrity, cell membrane stability, and hormonal precursor role - Synthesized in astrocytes, primarily from glucose and acetate, with minimal transport across the BBB - Cholesterol interacts with cell membrane lipids, forming lipid rafts that organize signaling molecules - High cholesterol levels linked to neuroinflammation, particularly in AD, due to disrupted lipid homeostasis - Research focuses on regulating brain cholesterol synthesis pathways and exploring peripheral lipid-lowering agents that might influence CNS cholesterol.(Jin et al. 2019 ) Bile Acid Synthesis in CNS - Bile acid synthesis enzyme from oxysterols is present in the CNS - CNS-specific bile acid synthesis suggests localized cholesterol metabolism distinct from liver bile acid synthesis in the periphery - Helps clear excess cholesterol, possibly mitigating buildup that could lead to inflammation - Enzyme CYP46 A1 produces bile acids from cholesterol precursors, aiding in brain cholesterol turnover - Interacts with oxysterol molecules that regulate bile acid levels within the CNS - Bile acids may reduce neuroinflammatory markers through receptor interactions like FXR and TGR5 in the brain - Studies are exploring bile acid receptor agonists for neuroprotection and the impact of bile acids on neuroinflammation in conditions like AD and MS.(Fleishman and Kumar 2024 ) Cholesterol Synthesis in Astrocytes - Astrocytes produce cholesterol from glucose, glutamine, and acetate - Astrocytes are the CNS’s main cholesterol source, while the liver serves this role in peripheral tissues - Supports neuronal health and plasticity, especially post-injury for neuron repair - Astrocytes synthesize cholesterol via the mevalonate pathway, starting from acetyl-CoA and ending with cholesterol - Uses enzyme HMG-CoA reductase, which interacts with intermediate molecules like mevalonate - Synthesis in astrocytes is upregulated in response to injury to support neurorepair, potentially reducing inflammation - Ongoing research includes astrocyte-targeted therapies to support neurorepair and address neuroinflammatory conditions through cholesterol modulation.(Papotti et al. 2022 ) Cholesterol Transport Mechanisms - Transported in blood by lipoproteins but restricted in CNS by the BBB; relies on HDL-like ApoE particles - CNS cholesterol transport uses ApoE-containing HDL, while periphery relies on LDL, HDL, and VLDL particles for transport - Facilitates distribution of cholesterol within CNS, supporting cellular repair and maintenance - ApoE and ABCA1 mediate cholesterol efflux in CNS, while HDL handles transport in blood circulation outside BBB - ApoE combines with lipid-binding proteins like ABCA1 to facilitate cholesterol movement within the brain - Efficient transport reduces lipid buildup that could lead to inflammation; inefficient transport linked to AD plaques - Research examines enhancing ApoE function for better cholesterol transport and clearance, targeting neurodegeneration and neuroinflammation reduction.(Borràs, et al. 2022 ; Razavi et al. 2025a ) ApoE Protein and Isoforms - CNS ApoE has three isoforms: ApoE2, ApoE3, and ApoE4, which vary in cholesterol transport efficiency - Isoform ApoE4 less efficient in cholesterol transport, linked to higher AD risk; ApoE2 associated with protective effects - Regulates cholesterol transport and neuronal repair, particularly post-injury - ApoE binds to receptors on neurons and glia to deliver cholesterol for maintenance and repair - ApoE interacts with LDLR and ABCA1, impacting cholesterol transport efficiency and cellular uptake - ApoE4 induces more inflammation due to inefficiencies in cholesterol transport and amyloid-beta plaque buildup in AD - Research is focusing on ApoE4-specific inhibitors, gene therapy, and lipid modulation strategies to reduce AD risk and inflammation.(Fakouri, et al. 2024 ) ApoE in Alzheimer’s Disease - ApoE4 carriers have a significantly higher AD risk, while ApoE2 carriers may have protective effects - ApoE4 less efficient in amyloid-beta clearance compared to ApoE2, leading to more plaque formation and inflammation - ApoE isoforms modulate amyloid-beta clearance, influencing AD progression - ApoE4 binds less effectively to amyloid-beta, resulting in greater plaque accumulation - ApoE4 interacts with receptors like LRP1 and fails to clear amyloid-beta as effectively as other isoforms - ApoE4’s inefficiency in amyloid-beta clearance exacerbates inflammation due to increased plaque presence - Targeting ApoE pathways to improve amyloid clearance, especially ApoE4 modulation, remains a major research focus in AD therapy.(Farokhi et al. 2024 ) Cholesterol Efflux and Regulation - LXR and RXR in astrocytes regulate cholesterol transport proteins at high cholesterol levels - CNS efflux through LXR/RXR and ABCA1 differs from peripheral tissues where efflux is mediated by HDL binding to ABCA1 - Facilitates cholesterol removal from cells to prevent buildup, supporting cell health - LXR and RXR bind to cholesterol response elements, activating genes for efflux proteins like ABCA1 - LXR/RXR complexes interact with ABCA1, promoting cholesterol removal from glial cells - Efficient efflux reduces cholesterol accumulation that could otherwise contribute to neuroinflammation - Research is exploring LXR/RXR agonists and ABCA1 upregulation for reducing cholesterol-induced neuroinflammation in CNS disorders.(Hatami et al. 2023a ; Men et al. 2024 ) Myelin Composition and Immune Response - Cholesterol-rich myelin is attacked by immune cells in MS, leading to demyelination - Myelin in CNS is uniquely cholesterol-rich, whereas peripheral tissues contain fewer cholesterol-based membranes - Provides insulation for neurons, enhancing signal transmission and CNS functionality - Cholesterol is necessary for myelin formation and repair, interacting with oligodendrocytes to maintain myelin - Myelin interacts with oligodendrocytes for formation and repair; debris accumulates without proper clearance - Demyelination in MS causes immune activation and inflammation, harming neuron health and CNS signaling - Therapeutic strategies focus on remyelination, oligodendrocyte support, and immune modulation to treat MS-related demyelination and inflammation.(López-Muguruza and Matute 2023 ) Microglial Role in Myelin Repair - Microglia clear cholesterol-rich myelin debris after injury, aiding in oligodendrocyte repair and differentiation - CNS microglia play a specialized role in neuroinflammation and repair, distinct from peripheral macrophages - Microglia act as CNS immune cells, managing debris clearance and inflammation - Phagocytize myelin debris, clear inflammatory signals, and create a reparative environment for oligodendrocytes - Interact with TREM2 receptors, which regulate phagocytosis and inflammation in CNS - Insufficient microglial activity in debris clearance can lead to prolonged inflammation and neurodegeneration - Current research explores enhancing microglial phagocytic activity to promote myelin repair and reduce neuroinflammation in diseases like MS and AD.(Hatami et al. 2023b ) Oxysterols in Neurodegenerative Disease - CYP27 A1 and CYP46 A1 enzymes convert cholesterol into oxysterols (27-OHC in blood, 24-OHC in CNS), affecting cholesterol homeostasis - CNS relies on CYP46 A1 for cholesterol turnover, producing oxysterols as by-products; peripheral oxysterol production largely involves CYP27 A1 - Oxysterols help remove excess cholesterol from the brain, maintaining cellular health - Oxysterols interact with liver X receptors (LXRs), aiding in cholesterol efflux and turnover - Oxysterols like 24-OHC bind to receptors like LXR and TGR5, influencing cellular lipid metabolism - Excess oxysterols, especially 24-OHC, trigger neuroinflammation and neuronal damage in neurodegenerative conditions - Studies are investigating LXR agonists to modulate oxysterol levels and reduce neuroinflammation, especially in AD and Parkinson’s disease.(Karimi Rouzbahani, et al. 2024 ) Effects on Oligodendrocytes and Myelin - Oligodendrocytes produce large amounts of cholesterol for myelin; 24-OHC can damage fats, reducing cholesterol precursors, and impairing myelin integrity - Oligodendrocytes are specialized for CNS myelin synthesis and repair; no peripheral analog exists for this cholesterol synthesis role - Synthesize and maintain myelin for neuronal insulation and signal conduction - Oligodendrocytes rely on cholesterol for myelin formation; myelin debris clearance involves microglial support - Myelin interacts with oligodendrocytes for its maintenance; debris accumulation affects their differentiation - Inflammatory conditions and myelin debris inhibit oligodendrocyte function, worsening demyelination - Focused on therapies promoting oligodendrocyte differentiation and myelin synthesis to support neuron repair in MS and AD-related demyelination.(Werkman et al. 2021 )

Table 1 Comprehensive table now includes an in-depth look at the mechanisms, interactions, and research directions across various aspects of cholesterol metabolism and its impact on the brain, neuroinflammation, and disease Factor Details Comparative notes Key functions Mechanisms of action Molecular interactions Impact on neuroinflammation Current research directions Cholesterol in the Brain - Brain contains 20% of body’s cholesterol, vital for immune regulation, signaling, myelin synthesis, and steroid hormone precursor - Synthesized locally in the brain due to BBB restrictions, unlike peripheral cholesterol which can be derived from diet - Maintains myelin integrity, cell membrane stability, and hormonal precursor role - Synthesized in astrocytes, primarily from glucose and acetate, with minimal transport across the BBB - Cholesterol interacts with cell membrane lipids, forming lipid rafts that organize signaling molecules - High cholesterol levels linked to neuroinflammation, particularly in AD, due to disrupted lipid homeostasis - Research focuses on regulating brain cholesterol synthesis pathways and exploring peripheral lipid-lowering agents that might influence CNS cholesterol.(Jin et al. 2019 ) Bile Acid Synthesis in CNS - Bile acid synthesis enzyme from oxysterols is present in the CNS - CNS-specific bile acid synthesis suggests localized cholesterol metabolism distinct from liver bile acid synthesis in the periphery - Helps clear excess cholesterol, possibly mitigating buildup that could lead to inflammation - Enzyme CYP46 A1 produces bile acids from cholesterol precursors, aiding in brain cholesterol turnover - Interacts with oxysterol molecules that regulate bile acid levels within the CNS - Bile acids may reduce neuroinflammatory markers through receptor interactions like FXR and TGR5 in the brain - Studies are exploring bile acid receptor agonists for neuroprotection and the impact of bile acids on neuroinflammation in conditions like AD and MS.(Fleishman and Kumar 2024 ) Cholesterol Synthesis in Astrocytes - Astrocytes produce cholesterol from glucose, glutamine, and acetate - Astrocytes are the CNS’s main cholesterol source, while the liver serves this role in peripheral tissues - Supports neuronal health and plasticity, especially post-injury for neuron repair - Astrocytes synthesize cholesterol via the mevalonate pathway, starting from acetyl-CoA and ending with cholesterol - Uses enzyme HMG-CoA reductase, which interacts with intermediate molecules like mevalonate - Synthesis in astrocytes is upregulated in response to injury to support neurorepair, potentially reducing inflammation - Ongoing research includes astrocyte-targeted therapies to support neurorepair and address neuroinflammatory conditions through cholesterol modulation.(Papotti et al. 2022 ) Cholesterol Transport Mechanisms - Transported in blood by lipoproteins but restricted in CNS by the BBB; relies on HDL-like ApoE particles - CNS cholesterol transport uses ApoE-containing HDL, while periphery relies on LDL, HDL, and VLDL particles for transport - Facilitates distribution of cholesterol within CNS, supporting cellular repair and maintenance - ApoE and ABCA1 mediate cholesterol efflux in CNS, while HDL handles transport in blood circulation outside BBB - ApoE combines with lipid-binding proteins like ABCA1 to facilitate cholesterol movement within the brain - Efficient transport reduces lipid buildup that could lead to inflammation; inefficient transport linked to AD plaques - Research examines enhancing ApoE function for better cholesterol transport and clearance, targeting neurodegeneration and neuroinflammation reduction.(Borràs, et al. 2022 ; Razavi et al. 2025a ) ApoE Protein and Isoforms - CNS ApoE has three isoforms: ApoE2, ApoE3, and ApoE4, which vary in cholesterol transport efficiency - Isoform ApoE4 less efficient in cholesterol transport, linked to higher AD risk; ApoE2 associated with protective effects - Regulates cholesterol transport and neuronal repair, particularly post-injury - ApoE binds to receptors on neurons and glia to deliver cholesterol for maintenance and repair - ApoE interacts with LDLR and ABCA1, impacting cholesterol transport efficiency and cellular uptake - ApoE4 induces more inflammation due to inefficiencies in cholesterol transport and amyloid-beta plaque buildup in AD - Research is focusing on ApoE4-specific inhibitors, gene therapy, and lipid modulation strategies to reduce AD risk and inflammation.(Fakouri, et al. 2024 ) ApoE in Alzheimer’s Disease - ApoE4 carriers have a significantly higher AD risk, while ApoE2 carriers may have protective effects - ApoE4 less efficient in amyloid-beta clearance compared to ApoE2, leading to more plaque formation and inflammation - ApoE isoforms modulate amyloid-beta clearance, influencing AD progression - ApoE4 binds less effectively to amyloid-beta, resulting in greater plaque accumulation - ApoE4 interacts with receptors like LRP1 and fails to clear amyloid-beta as effectively as other isoforms - ApoE4’s inefficiency in amyloid-beta clearance exacerbates inflammation due to increased plaque presence - Targeting ApoE pathways to improve amyloid clearance, especially ApoE4 modulation, remains a major research focus in AD therapy.(Farokhi et al. 2024 ) Cholesterol Efflux and Regulation - LXR and RXR in astrocytes regulate cholesterol transport proteins at high cholesterol levels - CNS efflux through LXR/RXR and ABCA1 differs from peripheral tissues where efflux is mediated by HDL binding to ABCA1 - Facilitates cholesterol removal from cells to prevent buildup, supporting cell health - LXR and RXR bind to cholesterol response elements, activating genes for efflux proteins like ABCA1 - LXR/RXR complexes interact with ABCA1, promoting cholesterol removal from glial cells - Efficient efflux reduces cholesterol accumulation that could otherwise contribute to neuroinflammation - Research is exploring LXR/RXR agonists and ABCA1 upregulation for reducing cholesterol-induced neuroinflammation in CNS disorders.(Hatami et al. 2023a ; Men et al. 2024 ) Myelin Composition and Immune Response - Cholesterol-rich myelin is attacked by immune cells in MS, leading to demyelination - Myelin in CNS is uniquely cholesterol-rich, whereas peripheral tissues contain fewer cholesterol-based membranes - Provides insulation for neurons, enhancing signal transmission and CNS functionality - Cholesterol is necessary for myelin formation and repair, interacting with oligodendrocytes to maintain myelin - Myelin interacts with oligodendrocytes for formation and repair; debris accumulates without proper clearance - Demyelination in MS causes immune activation and inflammation, harming neuron health and CNS signaling - Therapeutic strategies focus on remyelination, oligodendrocyte support, and immune modulation to treat MS-related demyelination and inflammation.(López-Muguruza and Matute 2023 ) Microglial Role in Myelin Repair - Microglia clear cholesterol-rich myelin debris after injury, aiding in oligodendrocyte repair and differentiation - CNS microglia play a specialized role in neuroinflammation and repair, distinct from peripheral macrophages - Microglia act as CNS immune cells, managing debris clearance and inflammation - Phagocytize myelin debris, clear inflammatory signals, and create a reparative environment for oligodendrocytes - Interact with TREM2 receptors, which regulate phagocytosis and inflammation in CNS - Insufficient microglial activity in debris clearance can lead to prolonged inflammation and neurodegeneration - Current research explores enhancing microglial phagocytic activity to promote myelin repair and reduce neuroinflammation in diseases like MS and AD.(Hatami et al. 2023b ) Oxysterols in Neurodegenerative Disease - CYP27 A1 and CYP46 A1 enzymes convert cholesterol into oxysterols (27-OHC in blood, 24-OHC in CNS), affecting cholesterol homeostasis - CNS relies on CYP46 A1 for cholesterol turnover, producing oxysterols as by-products; peripheral oxysterol production largely involves CYP27 A1 - Oxysterols help remove excess cholesterol from the brain, maintaining cellular health - Oxysterols interact with liver X receptors (LXRs), aiding in cholesterol efflux and turnover - Oxysterols like 24-OHC bind to receptors like LXR and TGR5, influencing cellular lipid metabolism - Excess oxysterols, especially 24-OHC, trigger neuroinflammation and neuronal damage in neurodegenerative conditions - Studies are investigating LXR agonists to modulate oxysterol levels and reduce neuroinflammation, especially in AD and Parkinson’s disease.(Karimi Rouzbahani, et al. 2024 ) Effects on Oligodendrocytes and Myelin - Oligodendrocytes produce large amounts of cholesterol for myelin; 24-OHC can damage fats, reducing cholesterol precursors, and impairing myelin integrity - Oligodendrocytes are specialized for CNS myelin synthesis and repair; no peripheral analog exists for this cholesterol synthesis role - Synthesize and maintain myelin for neuronal insulation and signal conduction - Oligodendrocytes rely on cholesterol for myelin formation; myelin debris clearance involves microglial support - Myelin interacts with oligodendrocytes for its maintenance; debris accumulation affects their differentiation - Inflammatory conditions and myelin debris inhibit oligodendrocyte function, worsening demyelination - Focused on therapies promoting oligodendrocyte differentiation and myelin synthesis to support neuron repair in MS and AD-related demyelination.(Werkman et al. 2021 )

Comprehensive table now includes an in-depth look at the mechanisms, interactions, and research directions across various aspects of cholesterol metabolism and its impact on the brain, neuroinflammation, and disease

RXR Family

Retinoic acid receptor (RAR) and retinoid X receptor (RXR) are two prominent retinoid families. Each family consists of three subtypes, α, β, and γ. These subtypes may exhibit splicing variants that can potentially lead to cancer or neurodegenerative diseases such as MS and Alzheimer’s disease (Hoog, et al. 2022 ; Andavar et al. 2025 ). The α isoform consists of 462 amino acids, with a molecular weight of 50,811 Da, and is placed on chromosome 9q34.2. It is found in the nucleus, cytoplasm, and mitochondria of cells. Alternative splicing can result in heterogeneity. A considerable subtype is typically present in the kidneys, liver, and intestine (Lefebvre et al. 2010 ). The β isoform is primarily located on chromosome 6p21.32, close to the HLA class II gene (Numasawa et al. 1999 ). In addition, it has been identified in endothelial cells and monocytes and is predominantly observed in various cancer cell lines (Sharma et al. 2022 ). The γ isoform is primarily localized in the gland, muscle, and brain. It spans 14 kb in length, contains nine introns with sizes ranging from 107 base pairs to 30 kb, and is situated on chromosome 1q23.3 (Sharma et al. 2022 ; Almeida and Conda-Sheridan 2019 ). RXR functions as a ligand-dependent transcription factor and regulates inflammation, metabolism, and immune response (Ting et al. 2020 ). In BALBcByJ mice, RXRγ-/-KO mice exhibit memory loss and depressive behavior (Wietrzych-Schindler et al. 2011 ; Kamrani et al. 2025 ). According to Zhou et al., RXR can play a role in suppressing inflammation by managing the NF-KB pathway or activating c-Jun kinase as a consequence of the c-Jun phosphorylation mechanism (Zhou et al. 2010 ; Zhang et al. 2015a ). However, the role of RXR signaling remains unclear. There are two primary types of RXR heterodimers. The first involves ligand-associated or permissive heterodimerization. These dimers work when they connect to RXR agonists or NR partners such as RXR/PPARγ, RXR/FXR, or RXR/LXR (Fig.  2 ). Fig. 2 A schematic showing the main genes that are active when RA is present. RA activates a number of genes, including those involved in cell differentiation and cancer cell proliferation, when it binds to its receptors, RAR, and RXR (Lavudi 2023 )

A schematic showing the main genes that are active when RA is present. RA activates a number of genes, including those involved in cell differentiation and cancer cell proliferation, when it binds to its receptors, RAR, and RXR (Lavudi 2023 )

These associations can enhance a synergistic biological response, resulting in the release of co-repressor proteins. In the second group, non-permissive heterodimerization, an agonist binds to the heterodimerization partner and initiates transcriptional activity. In this scenario, RXR acts as a subordinate or silent partner, as seen in the RXR/VDR and RXR/TR examples. RXR can bind and connect with coactivator proteins, whereas co-repressor proteins are released only when they bind to an RXR partner (Almeida and Conda-Sheridan 2019 ; Modi et al. 2013 ). Homodimers consist of RXR-RXRs. As a part of the heterodimeric complex, RXR is important for controlling transcriptional activity, especially in cell differentiation and metabolic processes, such as glucose and lipid metabolism. For example, heterodimerization occurs when RXR interacts with RAR (RXR-RAR) or another nuclear receptor. When it comes to RAR, RXR-RAR binds to a specific DNA sequence called RARE, which is found in the regulatory sequence of the target gene. Depending on the type of cell, promoter, and DNA-binding site, different cofactors control RXR-RAR activity. Similar to Jurutka, et al. ( 2021 ); Osz et al. 2020 ) Zhuang et al., 9-cis retinoic acid (9-cis-RA), a naturally occurring isomer of all-trans-retinoic acid (ATRA), is an RXR-specific ligand that acts as an agonist by binding to RXR and forcing the formation of RXR homodimers. This then causes RXR-responsive elements (RXREs) to activate or inhibit genes in the promoter region (Zhang et al. 1992 ). Metabolism happens in the central nervous system (CNS) and peripheral nervous system (PNS)(Sharma et al. 2022 ). In addition, 9-cis retinoic acid significantly enhanced remyelination in vivo after toxin-induced demyelination of cerebellar peduncles (Hanafy and Sloane 2011 ; Sadat Razavi, et al. 2025 ; Mehrnia 2024 ) (Table  2 ). Table 2 This expanded table covers the full range of details about the RAR and RXR families, their molecular characteristics, interactions, disease implications, and current research directions Factor Structure and location Function Mechanism of action Molecular interactions Implications in disease Impact on neuroinflammation Potential therapeutic applications Current research directions RAR and RXR Families - RAR and RXR families consist of three subtypes each: α, β, and γ - Found in cell nuclei and other cell compartments - Play roles in cellular differentiation, immune response, metabolism, and gene regulation - Act as ligand-activated transcription factors, controlling gene expression by binding to retinoid ligands and DNA sequences - Form dimers, either with each other or other nuclear receptors, to modulate transcription - Dysregulation can lead to cancers, MS, and Alzheimer’s due to disrupted cellular control - Abnormal activity in RAR and RXR can increase inflammatory signaling in the CNS, contributing to neurodegeneration - Targeted in cancer therapies and treatments for neurodegenerative and metabolic diseases - Ongoing studies focus on receptor modulation for cancer, neuroinflammation, and metabolic disorders.(Maire et al. 2019 ) RAR-α Isoform - 462 amino acids, located on chromosome 9q34.2 with molecular weight ~ 50,811 Da - Located in various cell compartments - Regulates gene expression, especially in organs like liver, kidney, and intestines - Acts as a transcription factor that binds DNA in response to specific retinoid ligands - Interacts with DNA and retinoic acid response elements (RAREs) to control gene transcription - Disruptions in RAR-α are linked to inflammatory diseases and certain cancers - Dysregulation can promote inflammatory pathways in immune-related disorders - Target for therapies that modulate inflammation and cell growth - Research on RAR-α includes its use in cancer prevention and immune modulation.(Razavi 2024a ) RAR-β Isoform - Primarily located on chromosome 6p21.32, close to HLA class II genes - Present in endothelial and cancer cell lines - Regulates gene expression in immune cells and cancer cells, impacting immune response and cell growth - Functions as a transcription factor, binding specific DNA regions in endothelial and immune cells - Binds to DNA in regions linked to immune response and cell proliferation - Abnormal expression in cancers and inflammation-related disorders - Elevated levels can worsen inflammation and proliferation in autoimmune and cancer conditions - Used in therapies aimed at cancer and immune-related inflammatory conditions - Focuses on RAR-β’s therapeutic potential in immunology and cancer treatment.(Razavi, et al. 2024a ; Seyrani et al. 2021 ) RAR-γ Isoform - Located on chromosome 1q23.3 in glands, muscles, and brain - Gene length ~ 14 kb with nine introns - Plays a role in CNS development and differentiation, particularly in the brain - Regulates gene expression in the CNS, binding to DNA to influence neurogenesis and neural health - Interacts with brain-specific DNA sequences for retinoic acid signaling pathways - Linked to neurodegenerative diseases like MS and AD due to its role in neural differentiation - Inadequate regulation can exacerbate neuroinflammation, impacting CNS health - Potential target for neurodegenerative therapies and neural differentiation support - Research focuses on RAR-γ’s applications in brain health, especially for neuroprotection and neurogenesis support.(Ren 2023 ) RXR Family - RXR family acts as ligand-dependent transcription factors, impacting metabolism, inflammation, and immune response - Found throughout the CNS and PNS - Regulates gene expression linked to lipid metabolism, immune response, and cell differentiation - RXR forms homodimers or heterodimers that, upon ligand binding, initiate transcription for immune and metabolic regulation - Interacts with nuclear receptors (e.g., PPAR, LXR) and signaling pathways (e.g., c-Jun, NF-KB) to regulate inflammation - Linked to memory loss, depression, and metabolic issues when dysfunction occurs - RXR dysregulation impacts neuroinflammatory pathways, contributing to cognitive and mood disorders - Modulation of RXR activity is explored for inflammation management and metabolic regulation - Studies are ongoing on RXR agonists for managing inflammation and mental health disorders.(Razavi, et al. 2024 ) RXR-α Isoform - Located in liver and adipose tissue; crucial for lipid and glucose metabolism - Plays a significant role in maintaining metabolic health, especially glucose and lipid processing - Functions as a transcription factor for lipid and glucose metabolism when bound to retinoic acid - Forms dimers with receptors like PPAR and LXR, affecting lipid and carbohydrate processing - Dysfunction linked to metabolic disorders, including diabetes and obesity - Metabolic dysregulation in RXR-α can indirectly increase systemic inflammation - Targeted for metabolic therapies, especially in diabetes and obesity treatments - Research on RXR-α centers on its role in metabolic syndrome and potential for diabetes management.(Qiu et al. 2023 ; Razavi et al. 2025b ) RXR-β Isoform - Distributed widely across organs including reproductive tissues and the CNS - Regulates immune response and cell proliferation, impacting inflammation and growth - Functions in a wide array of tissues, supporting immune function and growth regulation - Forms heterodimers with receptors like PPAR and FXR to regulate cellular proliferation and immune pathways - Abnormal RXR-β activity is linked to immune disorders and cancer growth - Overexpression may lead to inflammatory responses and unchecked cell proliferation - Targeted in therapies addressing immune system dysregulation and cell proliferation in cancer - Research focuses on RXR-β’s role in cancer therapies and immune modulation.(Razavi, et al. 2024b ) RXR-γ Isoform - Located primarily in brain, muscle, and immune cells - Linked to memory, mood, and immune regulation - Influences mental health and immune response, with implications in mood regulation and CNS function - RXR-γ functions as a transcription factor in neurons and immune cells, modulating CNS-related gene expression - Forms heterodimers that impact synaptic plasticity and neuron function - Dysfunction in RXR-γ is associated with neuropsychiatric disorders and memory loss - Dysregulation in RXR-γ can exacerbate neuroinflammation, impacting mental health - Targeted in therapies for depression and cognitive dysfunction, including memory disorders - Research on RXR-γ explores its potential in managing depression and neuroinflammation RXR Permissive Heterodimers - Includes RXR/PPARγ, RXR/FXR, and RXR/LXR dimers that bind both RXR agonists and NR partners - Key in regulating lipid, glucose, and bile acid metabolism, helping maintain metabolic homeostasis - RXR allows binding to either RXR or partner agonists, enhancing its regulatory flexibility - Forms permissive heterodimers that influence transcription, depending on ligand availability - Dysfunction in these pathways is linked to metabolic and liver diseases - Dysfunction can increase metabolic inflammation, impacting overall CNS health - Targeted with selective agonists for managing metabolic pathways, especially lipid and glucose levels - Research is focused on RXR-permissive heterodimer modulation for metabolic diseases RXR Non-Permissive Heterodimers - Includes RXR/VDR and RXR/TR dimers, where RXR acts as a silent partner requiring partner activation - Involved in calcium and thyroid hormone regulation, impacting bone health and metabolism - RXR partners only activate when their non-RXR agonist is present, resulting in selective transcriptional activity - Forms dimers with receptors like VDR and TR to control calcium and thyroid metabolism - Dysfunction affects thyroid and calcium homeostasis, leading to metabolic imbalances - Imbalances in calcium or thyroid levels may contribute to systemic inflammation - Targeted in therapies focused on bone health, vitamin D regulation, and thyroid hormone support - Research on RXR non-permissive heterodimers includes bone and thyroid health management.(Razavi 2024b ; Motavaselian et al. 2022 ) RXR Homodimers - RXR homodimers bind to RXREs and regulate transcription independently of other partners - Primarily involved in regulating lipid metabolism and cell differentiation - Activated by specific ligands, RXR homodimers bind RXREs directly to influence gene expression autonomously - RXR homodimers independently regulate genes tied to lipid metabolism and differentiation - Abnormal function leads to metabolic disorders and issues in cell differentiation - Dysregulated RXR homodimers can lead to increased metabolic inflammation, affecting lipid management in CNS - Explored in lipid disorder treatments and metabolic therapy development - Research on RXR homodimers includes studying their role in lipid metabolism and differentiation for therapeutic use.(Zhang et al. 2015b ) RXR-RAR Heterodimers - RXR binds with RAR to target RAREs in DNA, regulating gene expression across various cell types - Controls cellular differentiation, proliferation, and gene regulation, particularly in retinoid-responsive pathways - RXR-RAR binds to DNA sequences in response to cell type, ligand availability, and DNA-binding sites - RXR-RAR dimers interact with cofactors that vary depending on the cellular context and promoter involved - Disruption in RXR-RAR activity is linked to cancer, developmental issues, and metabolic problems - Dysregulated RXR-RAR dimers can increase inflammation due to poor differentiation and cell control - Explored as targets in cancer therapies and treatments aimed at differentiation and gene regulation modulation - Research focuses on RXR-RAR modulation for controlling cell proliferation and supporting cancer treatment.(Chatagnon et al. 2015 )

Table 2 This expanded table covers the full range of details about the RAR and RXR families, their molecular characteristics, interactions, disease implications, and current research directions Factor Structure and location Function Mechanism of action Molecular interactions Implications in disease Impact on neuroinflammation Potential therapeutic applications Current research directions RAR and RXR Families - RAR and RXR families consist of three subtypes each: α, β, and γ - Found in cell nuclei and other cell compartments - Play roles in cellular differentiation, immune response, metabolism, and gene regulation - Act as ligand-activated transcription factors, controlling gene expression by binding to retinoid ligands and DNA sequences - Form dimers, either with each other or other nuclear receptors, to modulate transcription - Dysregulation can lead to cancers, MS, and Alzheimer’s due to disrupted cellular control - Abnormal activity in RAR and RXR can increase inflammatory signaling in the CNS, contributing to neurodegeneration - Targeted in cancer therapies and treatments for neurodegenerative and metabolic diseases - Ongoing studies focus on receptor modulation for cancer, neuroinflammation, and metabolic disorders.(Maire et al. 2019 ) RAR-α Isoform - 462 amino acids, located on chromosome 9q34.2 with molecular weight ~ 50,811 Da - Located in various cell compartments - Regulates gene expression, especially in organs like liver, kidney, and intestines - Acts as a transcription factor that binds DNA in response to specific retinoid ligands - Interacts with DNA and retinoic acid response elements (RAREs) to control gene transcription - Disruptions in RAR-α are linked to inflammatory diseases and certain cancers - Dysregulation can promote inflammatory pathways in immune-related disorders - Target for therapies that modulate inflammation and cell growth - Research on RAR-α includes its use in cancer prevention and immune modulation.(Razavi 2024a ) RAR-β Isoform - Primarily located on chromosome 6p21.32, close to HLA class II genes - Present in endothelial and cancer cell lines - Regulates gene expression in immune cells and cancer cells, impacting immune response and cell growth - Functions as a transcription factor, binding specific DNA regions in endothelial and immune cells - Binds to DNA in regions linked to immune response and cell proliferation - Abnormal expression in cancers and inflammation-related disorders - Elevated levels can worsen inflammation and proliferation in autoimmune and cancer conditions - Used in therapies aimed at cancer and immune-related inflammatory conditions - Focuses on RAR-β’s therapeutic potential in immunology and cancer treatment.(Razavi, et al. 2024a ; Seyrani et al. 2021 ) RAR-γ Isoform - Located on chromosome 1q23.3 in glands, muscles, and brain - Gene length ~ 14 kb with nine introns - Plays a role in CNS development and differentiation, particularly in the brain - Regulates gene expression in the CNS, binding to DNA to influence neurogenesis and neural health - Interacts with brain-specific DNA sequences for retinoic acid signaling pathways - Linked to neurodegenerative diseases like MS and AD due to its role in neural differentiation - Inadequate regulation can exacerbate neuroinflammation, impacting CNS health - Potential target for neurodegenerative therapies and neural differentiation support - Research focuses on RAR-γ’s applications in brain health, especially for neuroprotection and neurogenesis support.(Ren 2023 ) RXR Family - RXR family acts as ligand-dependent transcription factors, impacting metabolism, inflammation, and immune response - Found throughout the CNS and PNS - Regulates gene expression linked to lipid metabolism, immune response, and cell differentiation - RXR forms homodimers or heterodimers that, upon ligand binding, initiate transcription for immune and metabolic regulation - Interacts with nuclear receptors (e.g., PPAR, LXR) and signaling pathways (e.g., c-Jun, NF-KB) to regulate inflammation - Linked to memory loss, depression, and metabolic issues when dysfunction occurs - RXR dysregulation impacts neuroinflammatory pathways, contributing to cognitive and mood disorders - Modulation of RXR activity is explored for inflammation management and metabolic regulation - Studies are ongoing on RXR agonists for managing inflammation and mental health disorders.(Razavi, et al. 2024 ) RXR-α Isoform - Located in liver and adipose tissue; crucial for lipid and glucose metabolism - Plays a significant role in maintaining metabolic health, especially glucose and lipid processing - Functions as a transcription factor for lipid and glucose metabolism when bound to retinoic acid - Forms dimers with receptors like PPAR and LXR, affecting lipid and carbohydrate processing - Dysfunction linked to metabolic disorders, including diabetes and obesity - Metabolic dysregulation in RXR-α can indirectly increase systemic inflammation - Targeted for metabolic therapies, especially in diabetes and obesity treatments - Research on RXR-α centers on its role in metabolic syndrome and potential for diabetes management.(Qiu et al. 2023 ; Razavi et al. 2025b ) RXR-β Isoform - Distributed widely across organs including reproductive tissues and the CNS - Regulates immune response and cell proliferation, impacting inflammation and growth - Functions in a wide array of tissues, supporting immune function and growth regulation - Forms heterodimers with receptors like PPAR and FXR to regulate cellular proliferation and immune pathways - Abnormal RXR-β activity is linked to immune disorders and cancer growth - Overexpression may lead to inflammatory responses and unchecked cell proliferation - Targeted in therapies addressing immune system dysregulation and cell proliferation in cancer - Research focuses on RXR-β’s role in cancer therapies and immune modulation.(Razavi, et al. 2024b ) RXR-γ Isoform - Located primarily in brain, muscle, and immune cells - Linked to memory, mood, and immune regulation - Influences mental health and immune response, with implications in mood regulation and CNS function - RXR-γ functions as a transcription factor in neurons and immune cells, modulating CNS-related gene expression - Forms heterodimers that impact synaptic plasticity and neuron function - Dysfunction in RXR-γ is associated with neuropsychiatric disorders and memory loss - Dysregulation in RXR-γ can exacerbate neuroinflammation, impacting mental health - Targeted in therapies for depression and cognitive dysfunction, including memory disorders - Research on RXR-γ explores its potential in managing depression and neuroinflammation RXR Permissive Heterodimers - Includes RXR/PPARγ, RXR/FXR, and RXR/LXR dimers that bind both RXR agonists and NR partners - Key in regulating lipid, glucose, and bile acid metabolism, helping maintain metabolic homeostasis - RXR allows binding to either RXR or partner agonists, enhancing its regulatory flexibility - Forms permissive heterodimers that influence transcription, depending on ligand availability - Dysfunction in these pathways is linked to metabolic and liver diseases - Dysfunction can increase metabolic inflammation, impacting overall CNS health - Targeted with selective agonists for managing metabolic pathways, especially lipid and glucose levels - Research is focused on RXR-permissive heterodimer modulation for metabolic diseases RXR Non-Permissive Heterodimers - Includes RXR/VDR and RXR/TR dimers, where RXR acts as a silent partner requiring partner activation - Involved in calcium and thyroid hormone regulation, impacting bone health and metabolism - RXR partners only activate when their non-RXR agonist is present, resulting in selective transcriptional activity - Forms dimers with receptors like VDR and TR to control calcium and thyroid metabolism - Dysfunction affects thyroid and calcium homeostasis, leading to metabolic imbalances - Imbalances in calcium or thyroid levels may contribute to systemic inflammation - Targeted in therapies focused on bone health, vitamin D regulation, and thyroid hormone support - Research on RXR non-permissive heterodimers includes bone and thyroid health management.(Razavi 2024b ; Motavaselian et al. 2022 ) RXR Homodimers - RXR homodimers bind to RXREs and regulate transcription independently of other partners - Primarily involved in regulating lipid metabolism and cell differentiation - Activated by specific ligands, RXR homodimers bind RXREs directly to influence gene expression autonomously - RXR homodimers independently regulate genes tied to lipid metabolism and differentiation - Abnormal function leads to metabolic disorders and issues in cell differentiation - Dysregulated RXR homodimers can lead to increased metabolic inflammation, affecting lipid management in CNS - Explored in lipid disorder treatments and metabolic therapy development - Research on RXR homodimers includes studying their role in lipid metabolism and differentiation for therapeutic use.(Zhang et al. 2015b ) RXR-RAR Heterodimers - RXR binds with RAR to target RAREs in DNA, regulating gene expression across various cell types - Controls cellular differentiation, proliferation, and gene regulation, particularly in retinoid-responsive pathways - RXR-RAR binds to DNA sequences in response to cell type, ligand availability, and DNA-binding sites - RXR-RAR dimers interact with cofactors that vary depending on the cellular context and promoter involved - Disruption in RXR-RAR activity is linked to cancer, developmental issues, and metabolic problems - Dysregulated RXR-RAR dimers can increase inflammation due to poor differentiation and cell control - Explored as targets in cancer therapies and treatments aimed at differentiation and gene regulation modulation - Research focuses on RXR-RAR modulation for controlling cell proliferation and supporting cancer treatment.(Chatagnon et al. 2015 )

This expanded table covers the full range of details about the RAR and RXR families, their molecular characteristics, interactions, disease implications, and current research directions

- RAR and RXR families consist of three subtypes each: α, β, and γ

- Found in cell nuclei and other cell compartments

- 462 amino acids, located on chromosome 9q34.2 with molecular weight ~ 50,811 Da

- Located in various cell compartments

- Primarily located on chromosome 6p21.32, close to HLA class II genes

- Present in endothelial and cancer cell lines

- Located on chromosome 1q23.3 in glands, muscles, and brain

- Gene length ~ 14 kb with nine introns

- RXR family acts as ligand-dependent transcription factors, impacting metabolism, inflammation, and immune response

- Found throughout the CNS and PNS

- Located primarily in brain, muscle, and immune cells

- Linked to memory, mood, and immune regulation

RXR Homeostasis in Cholesterol Metabolism

Cholesterol, the most important sterol in mammals, is pivotal in fluidity, permeability, and signaling in cell membranes, and has divergent aspects in immunity and inflammation (Endo-Umeda and Makishima 2019 ). Cholesterol transportation is a vital mechanism for cellular homeostasis. ATP-binding cassette transporters (ABC), particularly ABCA1, ABCG1, ABCG4, and ABCG5, are responsible for transporting cholesterol. ABCA1 and ABCG1 are crucial cholesterol transporters in several cell types. They facilitate the removal of cholesterol and inhibit foam cell formation (Seeree et al. 2019 ). ABCA1 is mostly expressed in the liver, intestine, brain, and macrophages (Chen et al. 2022 ; Shamabadi et al. 2024 ). In a process called reverse cholesterol transport (RCT), extra cholesterol and phospholipids move from the cell to apolipoprotein A (apo) and apo E, which are the main components of HDL. Therefore, Cholesterol is transferred to nascent or mature high-density lipoprotein (HDL). These transporters, such as RXR, PPARγ, and LXR, are stimulated by NR transcription (Xu et al. 2023 ; Zhao et al. 2025 ). In vitro studies have demonstrated that ABCA1 and ABCG1 in the cell membrane are necessary to eliminate cholesterol and protect neurons by suppressing cell death, inflammation, and oxidative stress (Koldamova et al. 2014 ). Moreover, RXR agonists have been shown to enhance ABCA1 expression in cultured endothelial cells (Manzano et al. 2000 ; Kolseth et al. 2012 ). Furthermore, these RXR agonists have been shown to suppress inflammation in cultured microglia cells.

The ABCA1 transporter regulates lipid metabolism and axonal growth via its interaction with LDLR (Borràs, et al. 2022 ; Chen et al. 2023 ). In addition, ABCA1 dysfunction in the brain is associated with reduced apo E levels (Wolf et al. 2012 ). The liver has role in apoE secretion in lipid metabolism to enter the blood circulation, and apoE is mainly expressed and secreted by astrocytes. These astrocyte functions are controlled by LXR and RXR transcription factors, which boost the immune system during inflammation (Fernández-Calle et al. 2022 ). In addition, earlier studies have demonstrated that ABCG4 transfers cholesterol from cells to HDL and causes cell death. Several sterols, such as cholesterol, 7β-hydroxycholesterol, 7-ketocholesterol, and desmosterol, have been reported to bind to ABCG1 in cells that express ABCG1 (Xu et al. 2023 ; Hegyi et al. 2022 ; Motavaselian et al. 2024 ). The regulation of the immune response by the LXR and RXR transcription factors in astrocytes suggests their crucial role in the inflammatory process. Additionally, the identification of various sterols as substrates of ABCG1 highlights the diverse functions of this transporter in cholesterol transport and cell apoptosis.

RXR Signaling Role in Neuroinflammation

Neuroinflammation is a process that can contribute to neurodegeneration but should not be equated with it. It represents a response to disrupted homeostasis in the central nervous system (CNS), often triggered by pathogens or tissue injury, and involves various cells, including astrocytes and microglia (Teleanu, et al. 2022 ). Neuroinflammation is triggered by four essential factors: macrophage activation (microglia), increment of cytokine and chemokine levels, recruitment of peripheral immune cells, and local tissue damage (Woodburn et al. 2021 ). At the inflammatory response beginning in the brain, the higher level of peripheral leukocyte infiltration and immunogenic molecules, microglia, the product pro-inflammatory cytokines such as IL-16, TNF-a, IL-18, matrix metalloproteinase (MMP), reactive nitrogen species (RNS), reactive oxygen species (ROS), and chemokine (CCL2) will be started (Woodburn et al. 2021 ). Microglia, as resident brain macrophages, are capable of phagocytosis due to their amoeboid morphology, cleaning foreign organisms, and cellular debris, and increasing neurotoxicity by production of ROS via NADPH oxidase (Teleanu, et al. 2022 ; Jayaraj et al. 2019 ).

Astrocytes are housekeeping cells and have an obligation to regulate the CNS. Thus, they are involved in homeostasis, neurotrophic factor release, clearing transmitters, shuttle metabolites, and BBB formation (Jayaraj et al. 2019 ). Therefore, neuroinflammation and oxidative status can synergistically affect each other (Teleanu, et al. 2022 ).

RXR signaling has a neuroprotective role in dopaminergic neurons. The heterodimeric partner of RXR, NURR1, has been shown to improve dopaminergic neurons and several fields in the hippocampus and cerebral cortex (Wietrzych-Schindler et al. 2011 ). Moreover, it heterodimerizes RXR with a permissive partner to determine the unfolded protein response (UPR) and ER stress (Aranda and Pascual 2001 ).

RXR prompts PPARγ to manage oxidative stress responses and suppresses autophagy to improve NRF2 expression in epileptic conditions in vivo. Moreover, previous studies have shown that the PPARγ/RXR complex alleviates the mitochondrial stress response by increasing the expression of UCP2, eNOS, and mn SOD scavenger protein (Wietrzych-Schindler et al. 2011 ; Yu et al. 2008 ).

NURR1, a highly expressed nuclear receptor, is heterodimerized in the CNS with RXR, and this complex stimulates ligand LG-268 to induce neuroprotection in ventral midbrain cultures (Wallen-Mackenzie et al. 2003 ). It appears that synthesized NURR1/RXR/HX600 agonists can repress the expression of microglial pro-inflammatory cytokines and anticipate cell death due to inflammation (Loppi et al. 2018 ). Furthermore, this transcription complex is triggered in midbrain dopaminergic and Serotonergic neurogenesis correlated with the stimulation of PI3 TX3 and Wnt/β-catenin signaling (Zhang et al. 2015c ; Xu et al. 2016 ). Vassilatis et al. found that exposing the NURR1/RXR-α heterodimer as monotherapy for Parkinson’s disease may have a double function by expanding striatal dopamine levels and upregulating the NURR1 target gene (Spathis et al. 2017 ; Lou et al. 2024 ). Likewise, it suppressed pro-inflammatory genes in LPS-treated astrocytes and microglia via the NF-KB pathway. It can be mentioned that RXRα separately impedes the β-catenin transcription and adjusts the WNT/β-catenin cascade in colon cancer, so this axis RXR- β-catenin is reported as a potential therapeutic target (Ruan et al. 2017 ).

RXR in MS

Expression of the retinoid X receptor (RXR), specifically RXR-γ, has been observed in MS lesions, and it has been noted that RXRs are activated within phagocytes in these lesions. These findings imply that RXR-γ is a significant physiological indicator of damage in acute injury in brain (Huang et al. 2011 ). RXR signaling is of great significance in remyelination and is closely linked to the regenerative reaction of the CNS. RXR-γ is typically expressed at nominal levels in all glial cells of intact mammalian CNS (Fig.  3 ). Fig. 3 Expression patterns and cellular location of endogenous RXR and SIRT6 in the brain following SAH are examined. an Analyses of quantitative western blot bands and the temporal course of RXR in the left hemisphere following SAH. b Quantitative analysis of the left hemisphere’s SIRT6 time course following SAH and representative western blot bands. **Compared to the control group (sham), *P < 0.05. The mean ± SD was used to illustrate the error bars. for each group, n  = 6. c At 24 h post-SAH, red-labeled neuronal (NeuN), astrocyte (GFAP), and microglia (Iba-1) cells in the left basal cortex were stained with double immunofluorescence for RXR (green). d Twenty-four hours following SAH, double immunofluorescence labeling for SIRT6 (red) in cells of the left basal cortex, specifically in neurons (NeuN, green), astrocytes (GFAP, green), and microglia (Iba-1, green). Each group has n  = 2. A 50 μm scale bar is used. Iba-1 is an ionized calcium binding adaptor molecule, NeuN is a neuronal nuclear protein, and DAPI is 4′,6-diamidino2-phenylindole. GFAP is a glial fibrillary acidic protein (Zuo et al. 2019 )

Expression patterns and cellular location of endogenous RXR and SIRT6 in the brain following SAH are examined. an Analyses of quantitative western blot bands and the temporal course of RXR in the left hemisphere following SAH. b Quantitative analysis of the left hemisphere’s SIRT6 time course following SAH and representative western blot bands. **Compared to the control group (sham), *P < 0.05. The mean ± SD was used to illustrate the error bars. for each group, n  = 6. c At 24 h post-SAH, red-labeled neuronal (NeuN), astrocyte (GFAP), and microglia (Iba-1) cells in the left basal cortex were stained with double immunofluorescence for RXR (green). d Twenty-four hours following SAH, double immunofluorescence labeling for SIRT6 (red) in cells of the left basal cortex, specifically in neurons (NeuN, green), astrocytes (GFAP, green), and microglia (Iba-1, green). Each group has n  = 2. A 50 μm scale bar is used. Iba-1 is an ionized calcium binding adaptor molecule, NeuN is a neuronal nuclear protein, and DAPI is 4′,6-diamidino2-phenylindole. GFAP is a glial fibrillary acidic protein (Zuo et al. 2019 )

However, after CNS injury, its expression intensifies in triggered microglia or macrophages, reactive astrocytes, and oligodendrocytes (Moreno et al. 2004 ; Schrage et al. 2006 ). The capacity of RXR to heterodimerize with a multitude of nuclear receptors implies that RXR can regulate the expression of a diverse array of genes, contingent on the timing and hetrodimerized receptor. RXR can form permissive and non-permissive heterodimers with various nuclear receptors (Altucci et al. 2007 ). Possible partners of permissive RXR-γ heterodimers include RXR-α, RXR-β, LXRα, COUP-TFI, and Nurr1 (Huang et al. 2011 ). Upregulation of LXR response genes, which serve as downstream targets of RXR, has been observed in phagocytes in active MS lesions. This finding suggests that RXR stimulation occurs in actively demyelinating phagocytes within MS lesions (Mailleux et al. 2018a ).

The obligatory formation of heterodimer complexes between liver X receptor alpha (LXR-α) and retinoid X receptors (RXR) is a significant aspect of molecular biology. These heterodimers bind to LXR response elements (LXREs) and subsequently regulate gene expression. Notably, the interactions between LXR-LBDs and RXRα-LBD can be considerably influenced by both LXR and RXR ligands (Yue et al. 2005 ; Wang et al. 2016 ).

The mediation of various facets of lipid metabolism is attributed to RXR and its associated partners, PPAR and LXR. The regulation of gene product expression for cholesterol transport, de novo synthesis, and catabolism is mediated by both LXR α and LXR β (Prüfer and Boudreaux 2007 ). The impact of LXR/RXR heterodimers on cholesterol metabolism in MS occurs through diverse mechanisms. The regulation of genes involved in cholesterol transport is overseen by LXR/RXR heterodimers (Murthy et al. 2002 ) as well as the regulation of genes implicated in de novo cholesterol production. LXRs are transcription factors sensitive to cholesterol, and their activation results in the upregulation of genes that mediate cholesterol (Zelcer and Tontonoz 2006 ). Moreover, LXR/RXR heterodimers have been found to significantly affect cholesterol catabolism by controlling the expression of genes involved in bile acid synthesis. Notably, the gene responsible for encoding 7α-hydroxylase, a crucial enzyme involved in bile acid synthesis, has been identified as a direct target of LXRs (Svensson et al. 2003 ). LXRs are crucial components in the integration of metabolic and inflammatory signaling pathways. The regulation of genes implicated in cholesterol metabolism and inflammation profoundly affects the metabolic state and immune response (Zelcer and Tontonoz 2006 ). According to previous research, LXRs, which necessitate the formation of a heterodimer with RXR, facilitate the promotion of myelin and remyelination in the cerebellum. This suggests a plausible role for LXR/RXR heterodimers in the regulation of myelination processes (Meffre et al. 2015 ). The investigation of RXR agonists, such as IRX4204, as a prospective therapy for MS and additional autoimmune disorders, is currently under investigation. This suggests that targeting RXR signaling may have therapeutic ramifications for treating MS (Chandraratna et al. 2016 ). The significance of RXR in MS is intricately linked to its dimerization with LXRα, and its value as a therapeutic target (Wang et al. 2016 ). The immunomodulatory effects of RXR agonists on human cells have been identified, and a novel RXR agonist is currently under development for treating MS and other autoimmune diseases (Gaunt et al. 2021 ) (Table  3 ). Table 3 This table summarizes the diverse functions of RXR signaling across cell types and mechanisms relevant to neuroinflammation and neurodegenerative conditions Aspect Details Key molecules/pathways Target cells Mechanism of action Disease/condition relevance Therapeutic implications Challenges and limitations RXR Role in Neuroinflammation RXR signaling promotes neuron health and neuroprotection, especially in dopaminergic neurons, by modulating inflammatory and oxidative pathways NURR1/RXR complex, PPARγ/RXR, UCP2, MnSOD Microglia, Astrocytes, Dopaminergic Neurons Modulates inflammatory response and reduces oxidative stress Parkinson’s disease, neurodegeneration Targeting RXR/NURR1 complexes may help reduce neurotoxicity Limited targeting specificity in different CNS areas (Al-Nusaif et al. 2022 ) RXR in Oxidative Stress RXR helps reduce oxidative damage by increasing antioxidant expression and suppressing cellular stress responses NRF2, PPARγ, UCP2, MnSOD Neurons, Microglia Enhances antioxidant defenses and regulates mitochondrial stress Epilepsy, neurodegeneration Potential to improve antioxidant defenses in neurodegenerative diseases Variability in efficacy depending on ROS sources (Ngo and Duennwald 2022 ) RXR and Microglial Activation RXR signaling suppresses pro-inflammatory cytokine production and oxidative stress in microglia IL-16, TNF-α, NF-kB pathway Microglia Decreases production of cytokines and ROS, limits neurotoxic inflammation Neuroinflammatory diseases, Alzheimer’s disease May reduce inflammation-driven neurodegeneration Effects vary based on microglial activation states (Qin et al. 2023 ) RXR and Astrocyte Function RXR regulates astrocytic inflammation, limiting excessive astrocyte activation and promoting CNS homeostasis NF-kB pathway, NURR1/RXR complex Astrocytes Controls inflammatory response, maintains BBB integrity (MS), Parkinson’s disease RXR modulation could maintain astrocytic balance and BBB function Potential for off-target effects on BBB and CNS cells (Sarmadi et al. 2024 ) RXR in (MS) RXR-γ expression increases in MS lesions and is important for CNS remyelination processes and repair RXR-γ, LXR/RXR complex, cholesterol transport genes Microglia, Phagocytes, Oligodendrocytes Supports remyelination and regulates lipid metabolism, reducing lesion formation Multiple sclerosis RXR agonists may promote repair and limit demyelination Requires sustained delivery for effective therapeutic action (Taheripak et al. 2024 ) RXR and Cholesterol Metabolism RXR/LXR complexes manage cholesterol synthesis, transport, and catabolism, essential for cellular membrane health in CNS cells LXR/RXR complex, cholesterol synthesis enzymes Oligodendrocytes, Phagocytes Regulates lipid balance, promotes membrane integrity and CNS cell health MS, neuroinflammatory conditions RXR-targeted therapies could support cellular lipid balance High cholesterol turnover may limit prolonged effect (Mahmoudvand et al. 2023 ) Therapeutic Potential of RXR RXR agonists are being developed to target inflammation, oxidative stress, and lipid dysregulation, aiming to slow neurodegeneration and promote CNS repair RXR-γ, NF-kB pathway, LXR/RXR complex, IRX4204 Microglia, Astrocytes, Oligodendrocytes, Neurons Reduces neuroinflammation, aids in remyelination, regulates lipid metabolism MS, Alzheimer’s, Parkinson’s disease Broad applications in neurodegeneration and autoimmune diseases Balancing anti-inflammatory and neuroprotective effects(Melchor et al. 2019 ) Challenges in RXR Targeting RXR’s multiple receptor interactions require selective targeting to avoid off-target effects, and it has different activation effects depending on the receptor partner RXR/NURR1, RXR/PPARγ, RXR/LXR complexes Various CNS cells Complexity of RXR signaling may cause differential effects across tissues Variable outcomes in different neuroinflammatory conditions Need for highly specific RXR agonists or antagonists Limited understanding of RXR effects across CNS regions RXR and Immune Cell Regulation RXR regulates immune cell activity in the CNS, reducing peripheral immune cell recruitment and controlling inflammation Chemokines, cytokines, NF-kB pathway, PPARγ/RXR Microglia, Peripheral Immune Cells Reduces inflammatory signals and peripheral immune cell infiltration Neuroinflammation, autoimmune CNS diseases Potential to reduce peripheral immune activation in the CNS Risk of broad immunosuppression in the body (Otaghvar, et al. 2019 ) RXR in ER Stress and Protein Folding RXR plays a role in regulating the unfolded protein response (UPR) and ER stress, which are key factors in cellular response to protein misfolding and inflammation RXR/NURR1, UPR genes, protein-folding chaperones CNS Cells, Microglia Enhances proper protein folding, reduces ER stress-induced inflammation Alzheimer’s, Parkinson’s, MS Could support cell health and reduce protein aggregation ER stress pathways can be difficult to target without side effects (Fernández 2021 ; Razavi 2024c ) RXR’s ability to form complexes with different nuclear receptors and regulate key processes like oxidative stress, cholesterol metabolism, and neuroinflammation highlights its therapeutic potential

Table 3 This table summarizes the diverse functions of RXR signaling across cell types and mechanisms relevant to neuroinflammation and neurodegenerative conditions Aspect Details Key molecules/pathways Target cells Mechanism of action Disease/condition relevance Therapeutic implications Challenges and limitations RXR Role in Neuroinflammation RXR signaling promotes neuron health and neuroprotection, especially in dopaminergic neurons, by modulating inflammatory and oxidative pathways NURR1/RXR complex, PPARγ/RXR, UCP2, MnSOD Microglia, Astrocytes, Dopaminergic Neurons Modulates inflammatory response and reduces oxidative stress Parkinson’s disease, neurodegeneration Targeting RXR/NURR1 complexes may help reduce neurotoxicity Limited targeting specificity in different CNS areas (Al-Nusaif et al. 2022 ) RXR in Oxidative Stress RXR helps reduce oxidative damage by increasing antioxidant expression and suppressing cellular stress responses NRF2, PPARγ, UCP2, MnSOD Neurons, Microglia Enhances antioxidant defenses and regulates mitochondrial stress Epilepsy, neurodegeneration Potential to improve antioxidant defenses in neurodegenerative diseases Variability in efficacy depending on ROS sources (Ngo and Duennwald 2022 ) RXR and Microglial Activation RXR signaling suppresses pro-inflammatory cytokine production and oxidative stress in microglia IL-16, TNF-α, NF-kB pathway Microglia Decreases production of cytokines and ROS, limits neurotoxic inflammation Neuroinflammatory diseases, Alzheimer’s disease May reduce inflammation-driven neurodegeneration Effects vary based on microglial activation states (Qin et al. 2023 ) RXR and Astrocyte Function RXR regulates astrocytic inflammation, limiting excessive astrocyte activation and promoting CNS homeostasis NF-kB pathway, NURR1/RXR complex Astrocytes Controls inflammatory response, maintains BBB integrity (MS), Parkinson’s disease RXR modulation could maintain astrocytic balance and BBB function Potential for off-target effects on BBB and CNS cells (Sarmadi et al. 2024 ) RXR in (MS) RXR-γ expression increases in MS lesions and is important for CNS remyelination processes and repair RXR-γ, LXR/RXR complex, cholesterol transport genes Microglia, Phagocytes, Oligodendrocytes Supports remyelination and regulates lipid metabolism, reducing lesion formation Multiple sclerosis RXR agonists may promote repair and limit demyelination Requires sustained delivery for effective therapeutic action (Taheripak et al. 2024 ) RXR and Cholesterol Metabolism RXR/LXR complexes manage cholesterol synthesis, transport, and catabolism, essential for cellular membrane health in CNS cells LXR/RXR complex, cholesterol synthesis enzymes Oligodendrocytes, Phagocytes Regulates lipid balance, promotes membrane integrity and CNS cell health MS, neuroinflammatory conditions RXR-targeted therapies could support cellular lipid balance High cholesterol turnover may limit prolonged effect (Mahmoudvand et al. 2023 ) Therapeutic Potential of RXR RXR agonists are being developed to target inflammation, oxidative stress, and lipid dysregulation, aiming to slow neurodegeneration and promote CNS repair RXR-γ, NF-kB pathway, LXR/RXR complex, IRX4204 Microglia, Astrocytes, Oligodendrocytes, Neurons Reduces neuroinflammation, aids in remyelination, regulates lipid metabolism MS, Alzheimer’s, Parkinson’s disease Broad applications in neurodegeneration and autoimmune diseases Balancing anti-inflammatory and neuroprotective effects(Melchor et al. 2019 ) Challenges in RXR Targeting RXR’s multiple receptor interactions require selective targeting to avoid off-target effects, and it has different activation effects depending on the receptor partner RXR/NURR1, RXR/PPARγ, RXR/LXR complexes Various CNS cells Complexity of RXR signaling may cause differential effects across tissues Variable outcomes in different neuroinflammatory conditions Need for highly specific RXR agonists or antagonists Limited understanding of RXR effects across CNS regions RXR and Immune Cell Regulation RXR regulates immune cell activity in the CNS, reducing peripheral immune cell recruitment and controlling inflammation Chemokines, cytokines, NF-kB pathway, PPARγ/RXR Microglia, Peripheral Immune Cells Reduces inflammatory signals and peripheral immune cell infiltration Neuroinflammation, autoimmune CNS diseases Potential to reduce peripheral immune activation in the CNS Risk of broad immunosuppression in the body (Otaghvar, et al. 2019 ) RXR in ER Stress and Protein Folding RXR plays a role in regulating the unfolded protein response (UPR) and ER stress, which are key factors in cellular response to protein misfolding and inflammation RXR/NURR1, UPR genes, protein-folding chaperones CNS Cells, Microglia Enhances proper protein folding, reduces ER stress-induced inflammation Alzheimer’s, Parkinson’s, MS Could support cell health and reduce protein aggregation ER stress pathways can be difficult to target without side effects (Fernández 2021 ; Razavi 2024c ) RXR’s ability to form complexes with different nuclear receptors and regulate key processes like oxidative stress, cholesterol metabolism, and neuroinflammation highlights its therapeutic potential

This table summarizes the diverse functions of RXR signaling across cell types and mechanisms relevant to neuroinflammation and neurodegenerative conditions

RXR’s ability to form complexes with different nuclear receptors and regulate key processes like oxidative stress, cholesterol metabolism, and neuroinflammation highlights its therapeutic potential

LXR

LXR, first discovered in the liver, has two isotypes, LXRα and LXRβ, which are encoded by NR1H3 and NR1H2, respectively. These two nuclear receptors function in hepatic lipid metabolism and are essential for lipogenesis because of their response to SREBP1, FASN, and SCD1 regulators. It also plays a role in phospholipid remodeling by controlling LPCAT3 expression. Moreover, other tissues control cholesterol homeostasis; hence, by heterodimerization with RXR and conjugation with a DNA sequence named LXR response element (LXREs) in the regulatory domain of the target gene, it induces genes involved in cholesterol homeostasis, including ABCA1, ABCG5, and ABCG8, and blocks LDL uptake via the IDL, thus improving cholesterol transfer to the bile salt. Stimulation of LXR by various types of oxysterols (such as 24(s)−25-epoxycholestrol, 20(s) hydroxy cholesterol, 22R-hydroxycholestrol, 24(s) hydroxy cholesterol, 7α-hydroxycholesterol, 25-hydroxycholstrol, and 27-hydroxyxholestrol) can induce lipoprotein gene expression, contain phospholipid transfer protein (PLTP), lipoprotein lipase (LPL), CETP, and apo E (Endo-Umeda and Makishima 2019 ; Griffett and Burris 2023 ) (Fig.  4 ). Fig. 4 When they bind to LXR response elements (LXREs) in the regulatory areas of the genes they target, liver X receptors (LXRs) and retinoid X receptors (RXRs) create heterodimers. Separated by four nucleotides (N), the target regions include variants of the repeating sequence AGGTCA. When ligands are not present, the LXR-RXR complex binds to co-repressors and shuts down gene expression. Oxysterols and synthetic ligands activate LXRs, and ligands for RXRs, like 9-cis-retinoic acid, activate RXRs, which in turn activate target genes involved in lipid metabolism by replacing co-repressors with co-activators. ASC2, histone acetyltransferase p300, NCoR, SMRT, and thyroid hormone receptor are all acronyms for activating signal co-integrator 2 and nuclear receptor co-repressor, respectively (Wang and Tontonoz 2018 )

When they bind to LXR response elements (LXREs) in the regulatory areas of the genes they target, liver X receptors (LXRs) and retinoid X receptors (RXRs) create heterodimers. Separated by four nucleotides (N), the target regions include variants of the repeating sequence AGGTCA. When ligands are not present, the LXR-RXR complex binds to co-repressors and shuts down gene expression. Oxysterols and synthetic ligands activate LXRs, and ligands for RXRs, like 9-cis-retinoic acid, activate RXRs, which in turn activate target genes involved in lipid metabolism by replacing co-repressors with co-activators. ASC2, histone acetyltransferase p300, NCoR, SMRT, and thyroid hormone receptor are all acronyms for activating signal co-integrator 2 and nuclear receptor co-repressor, respectively (Wang and Tontonoz 2018 )

Furthermore, LXR is involved in inflammation through a different mechanism, suppressing pro-inflammatory genes such as pro-inflammatory cytokines IL-1β and IL-6, inducible nitric oxide synthase (INOS), cyclooxygenase 2 (COX2), or signal-dependent transcription factors like the NF-KB pathway and activator protein 1 (Matalonga et al. 2017 ; Voisin, et al. 2020 ; Ramírez et al. 2021 ). Because LXR and its ligand exist in oligodendrocytes, mice lacking LXR had lower motor coordination and spatial learning, as well as a thinner myelin sheath, whereas stimulation of LXR by its ligand (whether 25-OHC or synthetic TO901317) resulted in higher expression of myelin gene and protein levels. Therefore, LXR controls the expression of myelin genes. Additionally, stimulation of LXR improves oligodendrocyte cell maturation and remyelination after induced demyelination in organotypic cerebellar slice cultures (Meffre et al. 2015 ). A study confirmed that mice with LXRα/β double knockout had some weakness in axonal atrophy and neuronal loss in ventral midbrain neurogenesis (Sacchetti et al. 2009 ). Beaven SW, in an in vitro and in vivo study, has shown that isolated HSC (hepatic satellite cell) LXR-/- animals had increased levels of collα1 and other pro-inflammatory cytokines (acta2, PDGFβ, and CCL2) compared to wild-type animals. Further analysis showed that exposure to a CCL4 or methionine-choline-deficient diet in LXR-/- mice increased α-SMA and collagen, respectively. Subsequently, LXR in wild-type HSC resulted in decreased levels of CCL2 and IL-6 and repressed the expression of the collα1 and acta genes (Beaven et al. 2011 ). Another role of LXR is the upregulation of the glucose transporter GLUT4 (Ikonen 2006 ); it has been shown that LXRα plays a significant role in the expression of GLUT4 in adipocytes and is a potential target in diabetes treatment (Bhattarai et al. 2021 ).

LXRα is primarily expressed in the liver, kidney, intestine, macrophages, and adipose tissues (Griffett and Burris 2023 ; Xie et al. 2022 ). Its gene is located on the short arm of chromosome 11 (11p11.2), which encodes a protein with 447 amino acids (Zhao et al. 2021 ). These capacities as cholesterol sensors were illustrated in a study in which LXRα-invalid mice were bolstered by high cholesterol and ate less. As for disability in LXR-dependent action, they cannot exchange cholesterol for bile salt (Peet et al. 1998 ). Likewise, another study showed that the loss of LXRα leads to cholesterol accumulation and a deficiency of cholesterol in bile acid (Wang and Tontonoz 2018 ). In contrast, LXRβ is expressed in several tissues. The LXR β gene is situated on the long arm of chromosome 19 (19q13.3), which encodes a protein with 460 amino acids (Zhao et al. 2021 ; Wang and Tontonoz 2018 ).

LXR in Cholesterol Homeostasis

The two main pathways regulating cholesterol metabolism are the LXR and transcription factor SREBPs. With a decrease in intracellular cholesterol, SREBPs enter the nucleus to trigger the transcription of adipose and cholesterol synthesis-related genes to ameliorate the levels of cellular lipids and steroids. High levels of oxysterol or its metabolites in cells stimulate LXR transcription. Thus, LXR and SREBP organize a negative feedback loop to control cellular cholesterol metabolism (Guo et al. 2022 ). The other lipogenic process of LXR is performed with the commencement of SREBP1-c transcription. Increasing cholesterol levels can initiate LXR, and then LXR can activate SREBPs to stimulate fat synthesis (Yan, et al. 2021 ). As a result of LXR activation, the expression of ABCA1 and ABCG1 promotes cholesterol efflux and manage degradation of the LDL receptor by modifying E3 ubiquitin ligase to diminish cholesterol uptake (Guo et al. 2022 ).

24(s)-hydroxy cholesterol (24-OHC), the major oxysterol in the brain, is produced by hydroxylation of cholesterol by 24-hydroxylase (CYP46 A1), and this 24-OHC is cleaved from a neuron in an ABCA1-dependent pathway. It can also affect either pro-survival or pro-death factors in the neurons. Under high-concentration conditions of 24-OHC, LXR transcription is suppressed to ameliorate necroptosis-like death pathways in neurons (Endo-Umeda and Makishima 2019 ). Evidence has revealed that 24-OHC and 25-epoxycholestrol play a role in the development of midbrain dopaminergic neurogenesis through LXR (Theofilopoulos et al. 2019 ; Theofilopoulos et al. 2013 ; Wang et al. 2024 ) (Table  4 ). Table 4 This table summarizes the diverse roles of LXR isoforms in lipid metabolism, cholesterol homeostasis, inflammation, and CNS health, highlighting their therapeutic potential across metabolic, inflammatory, and neurodegenerative diseases Aspect Description LXR isoforms Tissue distribution Key pathways/molecules Primary function Molecular effects Cell/tissue impact Role in disease/condition Therapeutic potential Limitations and challenges Isoform Characteristics LXR has two isotypes: LXRα (NR1H3) and LXRβ (NR1H2) LXRα, LXRβ LXRα: Liver, intestine, macrophages, adipose tissue; LXRβ: Systemic (most tissues) - LXRα: Primarily in lipid and cholesterol metabolism; LXRβ: Systemic roles in lipid homeostasis LXRα: Localized lipid and cholesterol regulation; LXRβ: Systemic effects Liver-specific in LXRα; widespread in LXRβ LXRα in liver, LXRβ in systemic conditions Isoform-specific therapies for targeted action Specific tissue activation is challenging to control Lipid Metabolism and Lipogenesis Essential for lipid synthesis and metabolism, regulating phospholipid remodeling and lipid storage LXRα Liver, adipose tissue SREBP1, FASN, SCD1, LPCAT3 Enhances lipogenesis by increasing expression of lipogenic enzymes Promotes fatty acid synthesis and lipid accumulation Adipocytes, hepatocytes Obesity, fatty liver disease Potential to manage lipid disorders and obesity Risk of exacerbating lipid accumulation Cholesterol Homeostasis Controls cholesterol transport, efflux, and bile conversion, limiting cellular cholesterol buildup LXRα, LXRβ Liver, macrophages (LXRα); systemic (LXRβ) ABCA1, ABCG5, ABCG8, LDL receptor, RXR, LXRE Facilitates cholesterol efflux and limits LDL uptake Increases bile salt conversion, reduces cholesterol uptake Hepatocytes, macrophages Atherosclerosis, cardiovascular diseases Helps reduce atherosclerosis by managing cholesterol levels Precise dosing needed to avoid systemic cholesterol loss Oxysterol Activation Activated by various oxysterols that enhance lipid and cholesterol transport pathways LXRα, LXRβ Liver, brain, macrophages, neurons 24(s)−25-epoxycholesterol, 22R-hydroxycholesterol, 25-hydroxycholesterol Responds to cholesterol derivatives to stimulate lipid transport Enhances transport of lipoproteins, phospholipid transfer protein (PLTP) Hepatocytes, neurons Atherosclerosis, neurodegenerative conditions Supports lipid transport therapies in cardiovascular health Limited control over oxysterol activation sites Inflammation and Immune Modulation Regulates inflammatory response by suppressing pro-inflammatory gene expression LXRα, LXRβ Immune cells (macrophages, microglia) IL-1β, IL-6, iNOS, COX2, NF-kB, AP-1 Reduces inflammation and cytokine production Downregulates inflammatory genes Microglia, macrophages Autoimmune diseases, neuroinflammatory conditions Anti-inflammatory role beneficial for chronic inflammation Potential risk of immune suppression Myelination and Neural Function Promotes myelin gene expression, aiding in remyelination and oligodendrocyte development LXRα, LXRβ Oligodendrocytes, CNS neurons Myelin genes, 25-OHC, TO901317 Stimulates myelin synthesis and remyelination in CNS Increases oligodendrocyte maturation and myelin repair CNS, oligodendrocytes Multiple sclerosis, demyelinating diseases Therapeutic potential in remyelination therapy for MS Complex CNS delivery for effective treatment Neurogenesis and Brain Health Supports neuron survival and neurogenesis, particularly in the midbrain LXRα, LXRβ Midbrain neurons 24-OHC, neurotrophic factors Promotes survival and differentiation of neurons Enhances neurogenesis, axonal growth Midbrain neurons Parkinson’s disease, neurodevelopmental disorders Promising target for neurogenesis and brain repair therapies CNS specificity is challenging to achieve SREBP Interaction and Feedback Regulation Works with SREBP to maintain cholesterol levels via a feedback loop in lipid metabolism LXRα, LXRβ Liver, adipose tissue SREBPs, ABCA1, ABCG1, LDL receptor Regulates lipid synthesis in response to cholesterol levels Coordinates cholesterol uptake and efflux Adipocytes, hepatocytes Hypercholesterolemia, cardiovascular disease Potential to control cholesterol in hyperlipidemia patients Overactivation may lead to lipid accumulation Fibrosis and Liver Inflammation Regulates hepatic stellate cells to reduce fibrosis and inflammation markers, promoting liver health LXRα Liver (hepatic stellate cells) Collα1, α-SMA, CCL2, IL-6 Suppresses fibrotic and inflammatory gene expression Lowers collagen and α-SMA expression in liver Hepatic stellate cells Liver fibrosis, chronic liver disease Anti-fibrotic potential for treating liver disease Risk of over-suppressing liver cell activation Glucose Transport and Metabolism LXRα regulates glucose transport in adipocytes, influencing GLUT4 expression LXRα Adipocytes, liver GLUT4 Enhances glucose uptake in adipocytes Increases GLUT4 expression, potentially aiding insulin sensitivity Adipocytes, liver cells Diabetes, insulin resistance Potential diabetes treatment by enhancing glucose uptake Risk of exacerbating insulin resistance if improperly targeted LXR in Cholesterol Efflux Regulation Directly promotes cholesterol efflux via regulation of transport proteins, maintaining cellular cholesterol balance LXRα, LXRβ Liver, macrophages, systemic cells ABCA1, ABCG1, E3 ubiquitin ligase Manages cellular cholesterol through efflux mechanisms Lowers intracellular cholesterol, prevents buildup Liver, macrophages Atherosclerosis, fatty liver disease Helps manage atherosclerosis by supporting cholesterol removal Effective control may require co-activation with other receptors Role in CNS Oxysterol Balance Maintains a balance of oxysterol levels in neurons, affecting survival and neurogenesis LXRβ Neurons, glial cells 24(s)-hydroxycholesterol (24-OHC), CYP46 A1 Regulates neuronal survival pathways related to oxysterol levels Modulates neuronal health by controlling oxysterol synthesis CNS neurons, glial cells Neurodegeneration, CNS oxidative stress LXRβ may protect against oxidative stress in neurodegenerative diseases CNS-specific targeting remains a challenge Systemic Metabolic Role of LXRβ LXRβ’s systemic expression allows it to act as a regulator of lipid balance throughout multiple tissues LXRβ Systemic distribution - Provides widespread lipid balance and cholesterol homeostasis Prevents systemic cholesterol overload and inflammation Most tissues Atherosclerosis, metabolic syndrome Systemic targeting could aid in metabolic syndrome treatment Avoiding over-suppression of cholesterol metabolism Genetic Knockout and Phenotypic Effects LXRα/β double knockout in mice shows deficits in motor coordination, myelination, and neural health, as well as liver lipid buildup LXRα, LXRβ Liver, CNS - Loss of LXR function leads to impaired cholesterol and lipid regulation Causes lipid accumulation, reduced myelination, inflammation Liver, CNS Neurodevelopmental, metabolic conditions Genetic understanding aids in designing isoform-targeted drugs Risk of side effects from gene-specific targeting

Table 4 This table summarizes the diverse roles of LXR isoforms in lipid metabolism, cholesterol homeostasis, inflammation, and CNS health, highlighting their therapeutic potential across metabolic, inflammatory, and neurodegenerative diseases Aspect Description LXR isoforms Tissue distribution Key pathways/molecules Primary function Molecular effects Cell/tissue impact Role in disease/condition Therapeutic potential Limitations and challenges Isoform Characteristics LXR has two isotypes: LXRα (NR1H3) and LXRβ (NR1H2) LXRα, LXRβ LXRα: Liver, intestine, macrophages, adipose tissue; LXRβ: Systemic (most tissues) - LXRα: Primarily in lipid and cholesterol metabolism; LXRβ: Systemic roles in lipid homeostasis LXRα: Localized lipid and cholesterol regulation; LXRβ: Systemic effects Liver-specific in LXRα; widespread in LXRβ LXRα in liver, LXRβ in systemic conditions Isoform-specific therapies for targeted action Specific tissue activation is challenging to control Lipid Metabolism and Lipogenesis Essential for lipid synthesis and metabolism, regulating phospholipid remodeling and lipid storage LXRα Liver, adipose tissue SREBP1, FASN, SCD1, LPCAT3 Enhances lipogenesis by increasing expression of lipogenic enzymes Promotes fatty acid synthesis and lipid accumulation Adipocytes, hepatocytes Obesity, fatty liver disease Potential to manage lipid disorders and obesity Risk of exacerbating lipid accumulation Cholesterol Homeostasis Controls cholesterol transport, efflux, and bile conversion, limiting cellular cholesterol buildup LXRα, LXRβ Liver, macrophages (LXRα); systemic (LXRβ) ABCA1, ABCG5, ABCG8, LDL receptor, RXR, LXRE Facilitates cholesterol efflux and limits LDL uptake Increases bile salt conversion, reduces cholesterol uptake Hepatocytes, macrophages Atherosclerosis, cardiovascular diseases Helps reduce atherosclerosis by managing cholesterol levels Precise dosing needed to avoid systemic cholesterol loss Oxysterol Activation Activated by various oxysterols that enhance lipid and cholesterol transport pathways LXRα, LXRβ Liver, brain, macrophages, neurons 24(s)−25-epoxycholesterol, 22R-hydroxycholesterol, 25-hydroxycholesterol Responds to cholesterol derivatives to stimulate lipid transport Enhances transport of lipoproteins, phospholipid transfer protein (PLTP) Hepatocytes, neurons Atherosclerosis, neurodegenerative conditions Supports lipid transport therapies in cardiovascular health Limited control over oxysterol activation sites Inflammation and Immune Modulation Regulates inflammatory response by suppressing pro-inflammatory gene expression LXRα, LXRβ Immune cells (macrophages, microglia) IL-1β, IL-6, iNOS, COX2, NF-kB, AP-1 Reduces inflammation and cytokine production Downregulates inflammatory genes Microglia, macrophages Autoimmune diseases, neuroinflammatory conditions Anti-inflammatory role beneficial for chronic inflammation Potential risk of immune suppression Myelination and Neural Function Promotes myelin gene expression, aiding in remyelination and oligodendrocyte development LXRα, LXRβ Oligodendrocytes, CNS neurons Myelin genes, 25-OHC, TO901317 Stimulates myelin synthesis and remyelination in CNS Increases oligodendrocyte maturation and myelin repair CNS, oligodendrocytes Multiple sclerosis, demyelinating diseases Therapeutic potential in remyelination therapy for MS Complex CNS delivery for effective treatment Neurogenesis and Brain Health Supports neuron survival and neurogenesis, particularly in the midbrain LXRα, LXRβ Midbrain neurons 24-OHC, neurotrophic factors Promotes survival and differentiation of neurons Enhances neurogenesis, axonal growth Midbrain neurons Parkinson’s disease, neurodevelopmental disorders Promising target for neurogenesis and brain repair therapies CNS specificity is challenging to achieve SREBP Interaction and Feedback Regulation Works with SREBP to maintain cholesterol levels via a feedback loop in lipid metabolism LXRα, LXRβ Liver, adipose tissue SREBPs, ABCA1, ABCG1, LDL receptor Regulates lipid synthesis in response to cholesterol levels Coordinates cholesterol uptake and efflux Adipocytes, hepatocytes Hypercholesterolemia, cardiovascular disease Potential to control cholesterol in hyperlipidemia patients Overactivation may lead to lipid accumulation Fibrosis and Liver Inflammation Regulates hepatic stellate cells to reduce fibrosis and inflammation markers, promoting liver health LXRα Liver (hepatic stellate cells) Collα1, α-SMA, CCL2, IL-6 Suppresses fibrotic and inflammatory gene expression Lowers collagen and α-SMA expression in liver Hepatic stellate cells Liver fibrosis, chronic liver disease Anti-fibrotic potential for treating liver disease Risk of over-suppressing liver cell activation Glucose Transport and Metabolism LXRα regulates glucose transport in adipocytes, influencing GLUT4 expression LXRα Adipocytes, liver GLUT4 Enhances glucose uptake in adipocytes Increases GLUT4 expression, potentially aiding insulin sensitivity Adipocytes, liver cells Diabetes, insulin resistance Potential diabetes treatment by enhancing glucose uptake Risk of exacerbating insulin resistance if improperly targeted LXR in Cholesterol Efflux Regulation Directly promotes cholesterol efflux via regulation of transport proteins, maintaining cellular cholesterol balance LXRα, LXRβ Liver, macrophages, systemic cells ABCA1, ABCG1, E3 ubiquitin ligase Manages cellular cholesterol through efflux mechanisms Lowers intracellular cholesterol, prevents buildup Liver, macrophages Atherosclerosis, fatty liver disease Helps manage atherosclerosis by supporting cholesterol removal Effective control may require co-activation with other receptors Role in CNS Oxysterol Balance Maintains a balance of oxysterol levels in neurons, affecting survival and neurogenesis LXRβ Neurons, glial cells 24(s)-hydroxycholesterol (24-OHC), CYP46 A1 Regulates neuronal survival pathways related to oxysterol levels Modulates neuronal health by controlling oxysterol synthesis CNS neurons, glial cells Neurodegeneration, CNS oxidative stress LXRβ may protect against oxidative stress in neurodegenerative diseases CNS-specific targeting remains a challenge Systemic Metabolic Role of LXRβ LXRβ’s systemic expression allows it to act as a regulator of lipid balance throughout multiple tissues LXRβ Systemic distribution - Provides widespread lipid balance and cholesterol homeostasis Prevents systemic cholesterol overload and inflammation Most tissues Atherosclerosis, metabolic syndrome Systemic targeting could aid in metabolic syndrome treatment Avoiding over-suppression of cholesterol metabolism Genetic Knockout and Phenotypic Effects LXRα/β double knockout in mice shows deficits in motor coordination, myelination, and neural health, as well as liver lipid buildup LXRα, LXRβ Liver, CNS - Loss of LXR function leads to impaired cholesterol and lipid regulation Causes lipid accumulation, reduced myelination, inflammation Liver, CNS Neurodevelopmental, metabolic conditions Genetic understanding aids in designing isoform-targeted drugs Risk of side effects from gene-specific targeting

This table summarizes the diverse roles of LXR isoforms in lipid metabolism, cholesterol homeostasis, inflammation, and CNS health, highlighting their therapeutic potential across metabolic, inflammatory, and neurodegenerative diseases

LXR Signaling in Neuroinflammation

The primary source of cholesterol in the brain arises from de novo biosynthesis. In the CNS of adult individuals, a significant proportion of cholesterol is situated in the lipid-rich myelin membranes (Björkhem et al. 2010 ; Dietschy 2009 ). The nuclear receptors play a fundamental role in various cellular mechanisms and are responsible for translating various metabolic, hormonal, and nutritional signals into alterations in gene expression (Calkin and Tontonoz 2012 ). LXRs play a crucial role in the regulation of the overall cholesterol homeostasis of the body, and oxysterol, being the natural ligand of LXR, effectively stimulates its activation (Calkin and Tontonoz 2012 ). Neuroinflammation is widely acknowledged as a crucial factor in the initiation and progression of neurodegenerative mechanisms, and several scholars have posited that the foundation of therapeutic intervention should involve the modulation of neuroinflammation (Bastias-Candia et al. 2016 ) (Fig.  5 ). Fig. 5 Bile acid, lipid, and glucose metabolism-related genes are targeted by FXR and LXR (Ding et al. 2014 )

Bile acid, lipid, and glucose metabolism-related genes are targeted by FXR and LXR (Ding et al. 2014 )

LXR agonists have demonstrated via the inhibition of Nuclear Factor Kappa B (NF-κB), a pivotal controller of inflammatory reactions, a propensity to diminish cerebral harm and mitigate neuroinflammatory response in intracerebral hemorrhage experimental models (Wu et al. 2016 ). LXR agonists repress neutrophil migration genes and neutrophil recruitment during inflammation, emphasizing the possible role of LXR agonists in suppressing inflammation (Thomas, et al. 2018 ). The LXRs are an essential signaling junction that connects lipid metabolism, inflammation, and neuroinflammation (Schulman 2017 ). In macrophages and other immune cells, the transcriptional role of pro-inflammatory genes is effectively repressed by LXRs (Schulman 2017 ). LXR agonists can repress the inflammatory responses elicited by microglia and astrocytes in the CNS. LXRs diminish the generation of pro-inflammatory agents, including IL-1β, IL-6, NO, iNOS, and MCP-1, in both microglia and astrocytes (Song et al. 2022 ). The isoforms of LXRα and LXRβ have been discovered to play a crucial role in preserving blood–brain barrier (BBB) function. Elevated activation of the LXR may be a potential treatment for intracerebral hemorrhage (ICH) and promote neuroprotection. This is achieved via the modulation of the cytotoxic activities of neuroinflammatory cells and, likewise, the regulation of BBB function during a neuroinflammatory insult (Wu et al. 2016 ; Wouters et al. 2019 ). Recent research has depicted the potential impact of LXR signaling on the pathology of Alzheimer’s disease (AD). By triggering LXR, it is possible to manage neuroinflammation and reduce the accumulation of amyloid-β peptide, thus offering promising therapeutic options for AD (Kang and Rivest 2012 ). The anti-inflammatory characteristic of LXRs may alleviate the capacity of microglia to phagocytose fAβ within an enduring inflammatory environment, thereby diminishing neuroinflammatory responses and attenuating the progression of Alzheimer’s disease pathology (Zelcer et al. 2007 ).

LXR regulates inflammatory gene expression in different ways: LXRs, through their activation and repression mechanisms, govern various facets of inflammatory gene expression in macrophages (Noelia and Castrillo 2011 ). Activation of LXR promotes cholesterol efflux and the repression of inflammatory genes, resulting in anti-atherogenic consequences (Thomas, et al. 2018 ).

Commencement of LXR has the potential to regulate inflammation in the CNS and impede the activity of nitric oxide synthase 2 in microglia (Secor McVoy et al. 2015 ). Previous research has indicated that LXR knockout animals exhibited heightened clinical disease severity during EAE. This phenomenon was attributed to the absence of inhibitory influence on lymphocyte Th17 lineage differentiation. Hence, it is apparent that LXR exerts physiological regulation over peripheral lymphocyte activation in the induction phase of EAE (Secor McVoy et al. 2015 ). LXRs are the main regulators of cholesterol homeostasis and inflammation in the CNS. LXRs probably serve as sensors that intricately regulate cholesterol turnover within the brain (Courtney and Landreth 2016 ). The LXRs are crucial in regulating the basal and inducible expression of cholesterol homeostatic genes in the brain. Furthermore, they exhibit remarkable potency as inhibitors of inflammatory gene expression (Zelcer et al. 2007 ). LXRs, due to their cholesterol-sensing and anti-inflammatory activities, hold a central position in the routine maintenance of CNS function (Courtney and Landreth 2016 ) (Table  5 ). Table 5 Comprehensive table summarizing the roles and mechanisms of Liver X Receptors (LXRs) in brain cholesterol homeostasis, inflammation regulation, neuroprotection, and neurodegenerative diseases, with multiple columns for detailed comparison Aspect Description LXR isoforms Tissue distribution Key molecules/pathways Primary function Molecular effects Role in CNS and disease Therapeutic potential Limitations and challenges Cholesterol Biosynthesis in the Brain Most brain cholesterol is synthesized de novo and is essential for myelin-rich membranes, especially in adult CNS LXRα, LXRβ Brain, specifically in myelin membranes Cholesterol synthesis pathways, oxysterols Maintains cholesterol balance in CNS Promotes cholesterol synthesis and turnover Essential for myelin stability, nerve function in the CNS Targeting LXRs may help manage cholesterol levels in neurodegeneration Difficult to control local synthesis without affecting peripheral tissues Role of Oxysterols in LXR Activation Oxysterols, as natural ligands, activate LXRs, initiating signaling pathways that regulate cholesterol homeostasis and inflammation LXRα, LXRβ Brain, liver, macrophages 24(s)-hydroxycholesterol, 25-hydroxycholesterol, other oxysterols Activates LXR to manage lipid and cholesterol levels Induces cholesterol efflux and controls lipid synthesis Balances lipid and cholesterol turnover in brain and periphery Can use oxysterol-based LXR agonists to regulate lipid metabolism Precise regulation is challenging due to widespread expression Neuroinflammation Modulation LXRs inhibit key inflammatory pathways, reducing production of pro-inflammatory molecules and suppressing immune cell activity LXRα, LXRβ Microglia, astrocytes, macrophages NF-κB, IL-1β, IL-6, NO, iNOS, MCP-1 Represses inflammation through cytokine and nitric oxide suppression Reduces pro-inflammatory cytokines, dampens NF-κB pathway Prevents neuroinflammatory damage in conditions like AD, MS Promising for managing neuroinflammation and neurodegeneration Prolonged suppression may affect normal immune responses Blood–Brain Barrier (BBB) Protection LXRs support BBB integrity by regulating genes that protect against neuroinflammatory cell damage LXRα, LXRβ Endothelial cells, astrocytes, microglia IL-1β, IL-6, TNF-α, MCP-1 Maintains BBB function under inflammatory stress Reduces inflammatory damage to BBB, enhances barrier integrity Important in conditions with BBB disruption, like ICH LXR activation may protect BBB in stroke and neuroinflammatory disease Requires precise BBB-targeted delivery Microglial and Astrocyte Inflammation Control LXR agonists decrease the production of pro-inflammatory molecules in CNS-resident immune cells like microglia and astrocytes LXRα, LXRβ Microglia, astrocytes IL-1β, IL-6, MCP-1, NO, iNOS Modulates neuroinflammation through immune cell activity Suppresses inflammatory gene expression, reduces NO and cytokines Reduces neuroinflammation, potentially slowing neurodegenerative diseases Potential for reducing inflammation in Alzheimer’s and MS Balancing suppression to avoid immune dysfunction Role in Alzheimer’s Disease (AD) LXR activation reduces amyloid-β accumulation and inflammation, helping mitigate AD pathology LXRα, LXRβ Neurons, microglia, astrocytes Amyloid-β peptide, NF-κB, IL-1β, iNOS, MCP-1 Reduces amyloid-β and inflammation Stimulates phagocytosis of amyloid-β by microglia, diminishes Aβ toxicity Attenuates neurodegeneration in AD through anti-inflammatory actions Targeting LXR may provide an anti-inflammatory and neuroprotective approach for AD Potential for long-term benefit is uncertain Inflammatory Gene Regulation in Macrophages LXR activation represses inflammatory gene transcription in macrophages and other immune cells, reducing systemic and CNS inflammation LXRα, LXRβ Macrophages, microglia NF-κB, IL-1β, COX2, iNOS Controls inflammatory response in immune cells Downregulates cytokines, nitric oxide, COX2 Limits systemic and CNS inflammation, supports CNS health Useful in chronic inflammation, cardiovascular disease, neuroinflammation May result in broad immune suppression Inhibition of Neutrophil Recruitment LXRs reduce the expression of neutrophil migration genes, limiting recruitment during inflammatory events LXRα, LXRβ Neutrophils, macrophages, microglia Chemokines, NF-κB Prevents excessive neutrophil recruitment and inflammation Inhibits chemotactic signaling for neutrophils Important in reducing acute and chronic inflammation May help control inflammation in CNS injuries and ICH Limiting neutrophil response may impair immune surveillance Impact on Experimental Autoimmune Encephalomyelitis (EAE) LXR knockouts show increased severity in EAE, highlighting its role in regulating lymphocyte and inflammatory responses LXRα, LXRβ Lymphocytes, macrophages, CNS Th17 cells, NF-κB, IL-6 Modulates peripheral immune response, Th17 differentiation Suppresses pro-inflammatory Th17 response in autoimmune contexts Could reduce neuroinflammatory and autoimmune responses in MS Useful in autoimmune CNS diseases by modulating peripheral lymphocytes Precise targeting needed to avoid systemic immune suppression Role in Neuroprotection and ICH LXRs protect CNS cells during ICH by reducing neuroinflammatory cell activity and preserving BBB function LXRα, LXRβ Neurons, endothelial cells, immune cells NF-κB, IL-1β, IL-6, BBB-associated genes Reduces neuroinflammation, protects neurons during ICH Lowers inflammatory cytokines, preserves BBB during neuroinflammatory insult Important in mitigating CNS damage in ICH and neuroinflammation LXR activation could reduce neuroinflammation and improve ICH outcomes Risk of over-suppressing inflammation during active infections Central Role in Linking Lipid Metabolism and Inflammation LXRs are crucial in coordinating lipid metabolism and inflammatory responses in the CNS and periphery LXRα, LXRβ Systemic tissues (liver, CNS) Cholesterol efflux pathways, NF-κB, inflammatory cytokines Regulates lipid levels, maintains inflammation balance Controls cholesterol turnover, reduces inflammation Essential for CNS lipid homeostasis, limiting neuroinflammatory responses LXR agonists may offer holistic benefits in metabolic and CNS diseases Risk of metabolic dysregulation if improperly dosed Regulation of Blood Cholesterol and Anti-Atherogenic Role LXRs help regulate cholesterol levels and prevent atherosclerosis by promoting cholesterol efflux and reducing inflammatory genes in macrophages LXRα, LXRβ Liver, macrophages, blood vessels ABCA1, ABCG1, NF-κB, cytokines Promotes cholesterol efflux, reduces inflammation in vessel walls Decreases macrophage foam cell formation, prevents lipid buildup Important for cardiovascular health, potentially beneficial in AD Could reduce atherosclerosis risk through lipid and inflammation control Broad activation may lead to widespread lipid regulation Role in Peripheral Lymphocyte Regulation LXR influences peripheral immune activation, particularly controlling Th17 cell differentiation in autoimmune diseases LXRα, LXRβ Lymphocytes, macrophages, CNS cells Th17 cells, NF-κB, IL-6 Suppresses Th17 activation, modulates immune response Prevents pro-inflammatory Th17 differentiation Reduces autoimmune neuroinflammatory responses in diseases like MS May reduce CNS and systemic inflammation in autoimmune diseases Balancing immune modulation to prevent excessive immune suppression LXR Knockout Effects LXR knockout animals show increased inflammation, impaired cholesterol regulation, and exacerbated neuroinflammatory responses, indicating LXR’s protective role LXRα, LXRβ Liver, brain, immune cells Th17 cells, NF-κB, inflammatory cytokines Loss of LXR function increases inflammation and dysregulates cholesterol Causes inflammation, increased cholesterol in CNS, immune dysfunction Highlights LXR’s essential role in CNS health and peripheral lipid control Basis for developing LXR-targeted therapies in inflammatory diseases Loss of both LXR isoforms disrupts essential metabolic processes

Table 5 Comprehensive table summarizing the roles and mechanisms of Liver X Receptors (LXRs) in brain cholesterol homeostasis, inflammation regulation, neuroprotection, and neurodegenerative diseases, with multiple columns for detailed comparison Aspect Description LXR isoforms Tissue distribution Key molecules/pathways Primary function Molecular effects Role in CNS and disease Therapeutic potential Limitations and challenges Cholesterol Biosynthesis in the Brain Most brain cholesterol is synthesized de novo and is essential for myelin-rich membranes, especially in adult CNS LXRα, LXRβ Brain, specifically in myelin membranes Cholesterol synthesis pathways, oxysterols Maintains cholesterol balance in CNS Promotes cholesterol synthesis and turnover Essential for myelin stability, nerve function in the CNS Targeting LXRs may help manage cholesterol levels in neurodegeneration Difficult to control local synthesis without affecting peripheral tissues Role of Oxysterols in LXR Activation Oxysterols, as natural ligands, activate LXRs, initiating signaling pathways that regulate cholesterol homeostasis and inflammation LXRα, LXRβ Brain, liver, macrophages 24(s)-hydroxycholesterol, 25-hydroxycholesterol, other oxysterols Activates LXR to manage lipid and cholesterol levels Induces cholesterol efflux and controls lipid synthesis Balances lipid and cholesterol turnover in brain and periphery Can use oxysterol-based LXR agonists to regulate lipid metabolism Precise regulation is challenging due to widespread expression Neuroinflammation Modulation LXRs inhibit key inflammatory pathways, reducing production of pro-inflammatory molecules and suppressing immune cell activity LXRα, LXRβ Microglia, astrocytes, macrophages NF-κB, IL-1β, IL-6, NO, iNOS, MCP-1 Represses inflammation through cytokine and nitric oxide suppression Reduces pro-inflammatory cytokines, dampens NF-κB pathway Prevents neuroinflammatory damage in conditions like AD, MS Promising for managing neuroinflammation and neurodegeneration Prolonged suppression may affect normal immune responses Blood–Brain Barrier (BBB) Protection LXRs support BBB integrity by regulating genes that protect against neuroinflammatory cell damage LXRα, LXRβ Endothelial cells, astrocytes, microglia IL-1β, IL-6, TNF-α, MCP-1 Maintains BBB function under inflammatory stress Reduces inflammatory damage to BBB, enhances barrier integrity Important in conditions with BBB disruption, like ICH LXR activation may protect BBB in stroke and neuroinflammatory disease Requires precise BBB-targeted delivery Microglial and Astrocyte Inflammation Control LXR agonists decrease the production of pro-inflammatory molecules in CNS-resident immune cells like microglia and astrocytes LXRα, LXRβ Microglia, astrocytes IL-1β, IL-6, MCP-1, NO, iNOS Modulates neuroinflammation through immune cell activity Suppresses inflammatory gene expression, reduces NO and cytokines Reduces neuroinflammation, potentially slowing neurodegenerative diseases Potential for reducing inflammation in Alzheimer’s and MS Balancing suppression to avoid immune dysfunction Role in Alzheimer’s Disease (AD) LXR activation reduces amyloid-β accumulation and inflammation, helping mitigate AD pathology LXRα, LXRβ Neurons, microglia, astrocytes Amyloid-β peptide, NF-κB, IL-1β, iNOS, MCP-1 Reduces amyloid-β and inflammation Stimulates phagocytosis of amyloid-β by microglia, diminishes Aβ toxicity Attenuates neurodegeneration in AD through anti-inflammatory actions Targeting LXR may provide an anti-inflammatory and neuroprotective approach for AD Potential for long-term benefit is uncertain Inflammatory Gene Regulation in Macrophages LXR activation represses inflammatory gene transcription in macrophages and other immune cells, reducing systemic and CNS inflammation LXRα, LXRβ Macrophages, microglia NF-κB, IL-1β, COX2, iNOS Controls inflammatory response in immune cells Downregulates cytokines, nitric oxide, COX2 Limits systemic and CNS inflammation, supports CNS health Useful in chronic inflammation, cardiovascular disease, neuroinflammation May result in broad immune suppression Inhibition of Neutrophil Recruitment LXRs reduce the expression of neutrophil migration genes, limiting recruitment during inflammatory events LXRα, LXRβ Neutrophils, macrophages, microglia Chemokines, NF-κB Prevents excessive neutrophil recruitment and inflammation Inhibits chemotactic signaling for neutrophils Important in reducing acute and chronic inflammation May help control inflammation in CNS injuries and ICH Limiting neutrophil response may impair immune surveillance Impact on Experimental Autoimmune Encephalomyelitis (EAE) LXR knockouts show increased severity in EAE, highlighting its role in regulating lymphocyte and inflammatory responses LXRα, LXRβ Lymphocytes, macrophages, CNS Th17 cells, NF-κB, IL-6 Modulates peripheral immune response, Th17 differentiation Suppresses pro-inflammatory Th17 response in autoimmune contexts Could reduce neuroinflammatory and autoimmune responses in MS Useful in autoimmune CNS diseases by modulating peripheral lymphocytes Precise targeting needed to avoid systemic immune suppression Role in Neuroprotection and ICH LXRs protect CNS cells during ICH by reducing neuroinflammatory cell activity and preserving BBB function LXRα, LXRβ Neurons, endothelial cells, immune cells NF-κB, IL-1β, IL-6, BBB-associated genes Reduces neuroinflammation, protects neurons during ICH Lowers inflammatory cytokines, preserves BBB during neuroinflammatory insult Important in mitigating CNS damage in ICH and neuroinflammation LXR activation could reduce neuroinflammation and improve ICH outcomes Risk of over-suppressing inflammation during active infections Central Role in Linking Lipid Metabolism and Inflammation LXRs are crucial in coordinating lipid metabolism and inflammatory responses in the CNS and periphery LXRα, LXRβ Systemic tissues (liver, CNS) Cholesterol efflux pathways, NF-κB, inflammatory cytokines Regulates lipid levels, maintains inflammation balance Controls cholesterol turnover, reduces inflammation Essential for CNS lipid homeostasis, limiting neuroinflammatory responses LXR agonists may offer holistic benefits in metabolic and CNS diseases Risk of metabolic dysregulation if improperly dosed Regulation of Blood Cholesterol and Anti-Atherogenic Role LXRs help regulate cholesterol levels and prevent atherosclerosis by promoting cholesterol efflux and reducing inflammatory genes in macrophages LXRα, LXRβ Liver, macrophages, blood vessels ABCA1, ABCG1, NF-κB, cytokines Promotes cholesterol efflux, reduces inflammation in vessel walls Decreases macrophage foam cell formation, prevents lipid buildup Important for cardiovascular health, potentially beneficial in AD Could reduce atherosclerosis risk through lipid and inflammation control Broad activation may lead to widespread lipid regulation Role in Peripheral Lymphocyte Regulation LXR influences peripheral immune activation, particularly controlling Th17 cell differentiation in autoimmune diseases LXRα, LXRβ Lymphocytes, macrophages, CNS cells Th17 cells, NF-κB, IL-6 Suppresses Th17 activation, modulates immune response Prevents pro-inflammatory Th17 differentiation Reduces autoimmune neuroinflammatory responses in diseases like MS May reduce CNS and systemic inflammation in autoimmune diseases Balancing immune modulation to prevent excessive immune suppression LXR Knockout Effects LXR knockout animals show increased inflammation, impaired cholesterol regulation, and exacerbated neuroinflammatory responses, indicating LXR’s protective role LXRα, LXRβ Liver, brain, immune cells Th17 cells, NF-κB, inflammatory cytokines Loss of LXR function increases inflammation and dysregulates cholesterol Causes inflammation, increased cholesterol in CNS, immune dysfunction Highlights LXR’s essential role in CNS health and peripheral lipid control Basis for developing LXR-targeted therapies in inflammatory diseases Loss of both LXR isoforms disrupts essential metabolic processes

Comprehensive table summarizing the roles and mechanisms of Liver X Receptors (LXRs) in brain cholesterol homeostasis, inflammation regulation, neuroprotection, and neurodegenerative diseases, with multiple columns for detailed comparison

LXR in MS

Cholesterol, the most dominant lipid present within myelin, performs a pivotal obligation in the myelination process (Saher et al. 2005 ). The Breakdown of myelin leads to an aberrant metabolism of cholesterol in the CNS among individuals with MS. This is evidenced by changes in the plasma concentrations of CNS-specific cholesterol metabolites (Kraats et al. 2014 ; Karrenbauer et al. 2006 ). Macrophages and resident microglia result in myelin phagocytosis, leading to an elevation in cholesterol absorption and the subsequent formation of intracellular oxysterols. Notably, metabolites of the cholesterol biosynthetic pathway serve as natural ligands for the LXR, stimulating cellular sterol efflux (Zhao and Dahlman-Wright 2009 ). CNS and immune cells express the LXRα and LXRβ isoforms (Fan et al. 2008 ; Joseph et al. 2004 ).

LXR signaling, particularly LXR activation, may play a role in MS by controlling cholesterol and lipid metabolism, modulating the inflammatory response, and potentially influencing disease progression (Wang et al. 2016 ). The upregulation of LXR response genes in phagocytes in active MS lesions indicates the stimulation of LXRs in actively demyelinating phagocytes. These data suggest the involvement of LXRs in the pathogenesis of MS (Mailleux et al. 2018b ). The activation of LXR in phagocytes within MS lesions is correlated with the absorption of myelin and the consequent generation of LXR ligands (Mailleux et al. 2018b ) in such a way that disruption of myelin by phagocytes is a crucial process in the development of MS (Mailleux et al. 2018b ). The myelin sheath is a layer abundant in cholesterol that envelops nerves. MS and other demyelinating diseases are characterized by the impairment of this safeguarding layer and the resulting deceleration of nerve impulses (Spady and Dietschy 1983 ). The breakdown of myelin leads to changes in the plasma levels of oxysterols specific to the central nervous system. These oxysterols serve as natural ligands for transcription factors known as LXRs. The process of myelin uptake by macrophages results in the activation of LXR in phagocytes by increasing the concentration of 27-hydroxycholesterol (27-OHC) and subsequently inducing response genes of LXR (ABCA1, ABCG1))(Ghisletti et al. 2007 ; Joseph et al. 2003 ). LXRs play a crucial role in the regulation of myelination and remyelination in oligodendrocytes by regulating the expression of genes involved in myelination, including proteolipid protein (PLP), myelin basic protein (MBP), and ATP-binding cassette subfamily G member 1 (ABCA1) (Song et al. 2022 ).

LXRs control the regulation of endogenous cholesterol levels in individuals with MS. The disruption of LXR-mediated pathways probably plays a role in the pathogenesis of MS (Pineda-Torra et al. 2021 ; Podbielska et al. 2021 ). The potential of LXR agonists has been demonstrated in various experimental models of Multiple Sclerosis. These agonists can alter the expression of cytokines and other immune mediators, as well as polarizing immune cells, ultimately improving clinical symptoms (Pineda-Torra et al. 2021 ).

Mutations affecting the NR1H3 gene, responsible for encoding LXRα, have been linked to familial MS, potentially impairing transcriptional regulation (Wang et al. 2016 ). The gene LXRα exhibits high levels of expression within the hepatic, adipose, intestinal, and differentiated macrophage tissues (A-Gonzalez, N.,, et al. 2013 ).

Certain findings have indicated that inducing LXRs in phagocytes could potentially have a favorable impact on the advancement of MS. The activation of LXR can modify the expression of cytokines and other immune mediators, consequently guiding immune cells toward anti-inflammatory phenotypes (Mailleux et al. 2018b ). The LXRs can reduce inflammatory responses in both macrophages and microglia. This suggests that the LXRs can regulate neuroinflammation and microglial activation (Mailleux et al. 2018b ).

The modulation of inflammation, stimulation of oligodendrocyte repair, and regulation of lipid metabolism are the core functions that LXR performs in MS. The activation of LXR has been identified as a promising therapeutic target for MS (Wang et al. 2016 ; Pineda-Torra et al. 2021 ; Jäger 2022 ) (Table  6 ). Table 6 This table provides an in-depth overview of the mechanisms through which LXRs affect MS progression, highlighting their functions in cholesterol metabolism, inflammation suppression, and myelination, as well as their therapeutic potential in MS management Aspect Description LXR Isoforms Tissue distribution Key pathways/molecules Primary functions in MS Molecular effects Disease mechanism in MS Therapeutic potential Limitations and challenges Cholesterol Role in Myelination Cholesterol is abundant in myelin and is essential for proper myelination and nerve function LXRα, LXRβ CNS (myelin sheaths, oligodendrocytes) Cholesterol, oxysterols Maintains myelin sheath integrity by regulating cholesterol levels Supports cholesterol synthesis and turnover in myelin Myelin breakdown disrupts cholesterol, leading to demyelination LXRs may help restore cholesterol homeostasis in demyelinated regions Controlling cholesterol locally without systemic effects Myelin Phagocytosis by Macrophages Macrophages and microglia phagocytize damaged myelin, increasing cholesterol absorption and oxysterol production LXRα, LXRβ Phagocytes (microglia, macrophage) Oxysterols, 27-hydroxycholesterol, cholesterol efflux genes (ABCA1, ABCG1) Promotes cholesterol efflux in phagocytes and reduces lipid accumulation Enhances clearance of cholesterol from phagocytes via efflux pathways Excessive myelin breakdown releases oxysterols, activating LXR in lesions Activation of LXRs may facilitate cholesterol removal from lesions Managing excessive cholesterol uptake and efflux in phagocytes LXR Activation by Myelin Breakdown Myelin degradation elevates CNS-specific oxysterols that activate LXRs, stimulating cholesterol efflux in demyelinating lesions LXRα, LXRβ Phagocytes (active in MS lesions) 27-hydroxycholesterol, ABCA1, ABCG1 LXR activation clears cholesterol from phagocytes Increases cholesterol efflux genes, reducing intracellular cholesterol Reduces cholesterol overload in demyelinating regions Supports lipid clearance in active MS lesions May require targeted delivery to prevent unintended effects Gene Expression in Myelination LXRs regulate myelin genes, aiding in myelination and repair in oligodendrocytes LXRα, LXRβ Oligodendrocytes Proteolipid protein (PLP), Myelin basic protein (MBP), ABCA1 Enhances expression of myelin-related proteins Promotes synthesis and repair of myelin proteins in the CNS Supports remyelination and nerve protection LXR agonists may promote myelin repair in demyelinating diseases Risk of ineffective remyelination without adequate targeting Neuroinflammation Modulation LXRs suppress inflammatory responses by downregulating pro-inflammatory gene expression in immune cells LXRα, LXRβ Microglia, macrophages Cytokines (IL-1β, IL-6), NF-κB, MCP-1 Reduces inflammation in MS by suppressing cytokine production Downregulates pro-inflammatory genes in immune cells Reduces microglial activation and inflammation in the CNS LXR agonists could lower inflammation and slow MS progression Balancing inflammation control with immune function is challenging Immune Cell Polarization LXR activation guides immune cells toward anti-inflammatory phenotypes, beneficial for MS LXRα, LXRβ Macrophages, microglia Cytokines, immune mediators Promotes anti-inflammatory immune response Alters cytokine expression, encourages anti-inflammatory phenotypes Reduces neuroinflammation and supports CNS health Potential to control immune cell behavior in MS Over-suppression of immune response may compromise pathogen defense Role in BBB Function LXRs protect and maintain the integrity of the blood–brain barrier (BBB), reducing neuroinflammatory cell damage LXRα, LXRβ Endothelial cells, astrocytes IL-1β, IL-6, BBB-associated genes Protects BBB under neuroinflammatory conditions Prevents breakdown of BBB, reduces immune cell infiltration Maintains BBB integrity, limits CNS exposure to systemic immune cells LXR activation may support BBB health in MS and neuroinflammatory states Targeting BBB-specific LXR activation without systemic effects is difficult Influence on Disease Progression LXR signaling helps control disease progression by regulating cholesterol, inflammation, and immune activity LXRα, LXRβ CNS (phagocytes, oligodendrocytes) LXR response genes, inflammatory pathways Modulates inflammation and cholesterol to limit MS progression Controls lipid overload and inflammatory responses in MS lesions Reduces myelin damage, neuroinflammation, and progression of MS LXR agonists may help slow MS progression and improve CNS function Long-term safety of LXR agonists in chronic use remains uncertain Impact of NR1H3 Mutation in Familial MS NR1H3 mutation, encoding LXRα, has been linked to familial MS, impairing transcriptional control LXRα Liver, adipose, CNS (phagocytes) NR1H3 gene, LXRα Disrupted NR1H3 impairs cholesterol and inflammatory gene regulation Reduces cholesterol transport and inflammatory control, worsening MS Increases susceptibility to MS via defective LXRα signaling LXR-based therapies may counteract effects of NR1H3 mutations in MS Requires genetic profiling to target specific mutations LXR and Oligodendrocyte Stimulation LXR signaling promotes oligodendrocyte maturation and remyelination, essential for MS recovery LXRα, LXRβ Oligodendrocytes Myelin proteins (PLP, MBP), ABCA1, ATP-binding cassette genes Stimulates oligodendrocyte activity and remyelination Increases expression of myelin genes, aids myelin sheath repair Supports CNS repair and remyelination in demyelinating lesions LXR agonists may enhance oligodendrocyte recovery in MS Ensuring remyelination without overactivation is challenging LXR Agonists in MS Experimental Models LXR agonists have shown to modulate cytokine expression, immune response, and improve clinical symptoms in MS models LXRα, LXRβ CNS (microglia, macrophages, astrocytes) Cytokines, immune mediators, myelin genes Alters immune cell behavior, enhances anti-inflammatory responses Reduces pro-inflammatory markers, promotes CNS homeostasis Decreases inflammation, supports neuroprotection and symptom management LXR agonists show promise in reducing MS symptoms Long-term effects of LXR agonists on CNS health are not fully known Modulation of Lipid and Cholesterol Metabolism LXR regulates cholesterol homeostasis, crucial for maintaining lipid balance in MS LXRα, LXRβ Phagocytes, oligodendrocytes Cholesterol efflux genes (ABCA1, ABCG1), oxysterols Enhances cholesterol efflux and reduces intracellular lipid buildup Decreases lipid overload in immune cells, prevents cytotoxicity Helps manage lipid overload due to myelin degradation Potential for lipid metabolism control in MS Achieving balance between lipid clearance and cell survival is complex Anti-inflammatory and Neuroprotective Role LXRs reduce neuroinflammatory responses in CNS cells, protecting against neurodegeneration LXRα, LXRβ Microglia, astrocytes IL-1β, IL-6, NF-κB, MCP-1 Controls inflammation, preserves neuron function Downregulates inflammatory gene expression in CNS immune cells Protects against neurodegenerative damage in CNS Targeting LXRs could provide neuroprotection in MS Risk of immunosuppression with prolonged LXR activation Clinical Relevance of LXR-Mediated Pathways LXR signaling modulates myelin repair, lipid metabolism, and immune regulation, crucial for MS management LXRα, LXRβ CNS and immune cells LXR response genes, inflammatory pathways, cholesterol metabolism genes Controls multiple MS-related pathways, influencing symptoms and progression Reduces demyelination, limits inflammation, and aids in repair processes Provides a comprehensive target for MS management LXR-targeted treatments may provide multi-faceted MS benefits Requires precise targeting to avoid broad systemic effects

Table 6 This table provides an in-depth overview of the mechanisms through which LXRs affect MS progression, highlighting their functions in cholesterol metabolism, inflammation suppression, and myelination, as well as their therapeutic potential in MS management Aspect Description LXR Isoforms Tissue distribution Key pathways/molecules Primary functions in MS Molecular effects Disease mechanism in MS Therapeutic potential Limitations and challenges Cholesterol Role in Myelination Cholesterol is abundant in myelin and is essential for proper myelination and nerve function LXRα, LXRβ CNS (myelin sheaths, oligodendrocytes) Cholesterol, oxysterols Maintains myelin sheath integrity by regulating cholesterol levels Supports cholesterol synthesis and turnover in myelin Myelin breakdown disrupts cholesterol, leading to demyelination LXRs may help restore cholesterol homeostasis in demyelinated regions Controlling cholesterol locally without systemic effects Myelin Phagocytosis by Macrophages Macrophages and microglia phagocytize damaged myelin, increasing cholesterol absorption and oxysterol production LXRα, LXRβ Phagocytes (microglia, macrophage) Oxysterols, 27-hydroxycholesterol, cholesterol efflux genes (ABCA1, ABCG1) Promotes cholesterol efflux in phagocytes and reduces lipid accumulation Enhances clearance of cholesterol from phagocytes via efflux pathways Excessive myelin breakdown releases oxysterols, activating LXR in lesions Activation of LXRs may facilitate cholesterol removal from lesions Managing excessive cholesterol uptake and efflux in phagocytes LXR Activation by Myelin Breakdown Myelin degradation elevates CNS-specific oxysterols that activate LXRs, stimulating cholesterol efflux in demyelinating lesions LXRα, LXRβ Phagocytes (active in MS lesions) 27-hydroxycholesterol, ABCA1, ABCG1 LXR activation clears cholesterol from phagocytes Increases cholesterol efflux genes, reducing intracellular cholesterol Reduces cholesterol overload in demyelinating regions Supports lipid clearance in active MS lesions May require targeted delivery to prevent unintended effects Gene Expression in Myelination LXRs regulate myelin genes, aiding in myelination and repair in oligodendrocytes LXRα, LXRβ Oligodendrocytes Proteolipid protein (PLP), Myelin basic protein (MBP), ABCA1 Enhances expression of myelin-related proteins Promotes synthesis and repair of myelin proteins in the CNS Supports remyelination and nerve protection LXR agonists may promote myelin repair in demyelinating diseases Risk of ineffective remyelination without adequate targeting Neuroinflammation Modulation LXRs suppress inflammatory responses by downregulating pro-inflammatory gene expression in immune cells LXRα, LXRβ Microglia, macrophages Cytokines (IL-1β, IL-6), NF-κB, MCP-1 Reduces inflammation in MS by suppressing cytokine production Downregulates pro-inflammatory genes in immune cells Reduces microglial activation and inflammation in the CNS LXR agonists could lower inflammation and slow MS progression Balancing inflammation control with immune function is challenging Immune Cell Polarization LXR activation guides immune cells toward anti-inflammatory phenotypes, beneficial for MS LXRα, LXRβ Macrophages, microglia Cytokines, immune mediators Promotes anti-inflammatory immune response Alters cytokine expression, encourages anti-inflammatory phenotypes Reduces neuroinflammation and supports CNS health Potential to control immune cell behavior in MS Over-suppression of immune response may compromise pathogen defense Role in BBB Function LXRs protect and maintain the integrity of the blood–brain barrier (BBB), reducing neuroinflammatory cell damage LXRα, LXRβ Endothelial cells, astrocytes IL-1β, IL-6, BBB-associated genes Protects BBB under neuroinflammatory conditions Prevents breakdown of BBB, reduces immune cell infiltration Maintains BBB integrity, limits CNS exposure to systemic immune cells LXR activation may support BBB health in MS and neuroinflammatory states Targeting BBB-specific LXR activation without systemic effects is difficult Influence on Disease Progression LXR signaling helps control disease progression by regulating cholesterol, inflammation, and immune activity LXRα, LXRβ CNS (phagocytes, oligodendrocytes) LXR response genes, inflammatory pathways Modulates inflammation and cholesterol to limit MS progression Controls lipid overload and inflammatory responses in MS lesions Reduces myelin damage, neuroinflammation, and progression of MS LXR agonists may help slow MS progression and improve CNS function Long-term safety of LXR agonists in chronic use remains uncertain Impact of NR1H3 Mutation in Familial MS NR1H3 mutation, encoding LXRα, has been linked to familial MS, impairing transcriptional control LXRα Liver, adipose, CNS (phagocytes) NR1H3 gene, LXRα Disrupted NR1H3 impairs cholesterol and inflammatory gene regulation Reduces cholesterol transport and inflammatory control, worsening MS Increases susceptibility to MS via defective LXRα signaling LXR-based therapies may counteract effects of NR1H3 mutations in MS Requires genetic profiling to target specific mutations LXR and Oligodendrocyte Stimulation LXR signaling promotes oligodendrocyte maturation and remyelination, essential for MS recovery LXRα, LXRβ Oligodendrocytes Myelin proteins (PLP, MBP), ABCA1, ATP-binding cassette genes Stimulates oligodendrocyte activity and remyelination Increases expression of myelin genes, aids myelin sheath repair Supports CNS repair and remyelination in demyelinating lesions LXR agonists may enhance oligodendrocyte recovery in MS Ensuring remyelination without overactivation is challenging LXR Agonists in MS Experimental Models LXR agonists have shown to modulate cytokine expression, immune response, and improve clinical symptoms in MS models LXRα, LXRβ CNS (microglia, macrophages, astrocytes) Cytokines, immune mediators, myelin genes Alters immune cell behavior, enhances anti-inflammatory responses Reduces pro-inflammatory markers, promotes CNS homeostasis Decreases inflammation, supports neuroprotection and symptom management LXR agonists show promise in reducing MS symptoms Long-term effects of LXR agonists on CNS health are not fully known Modulation of Lipid and Cholesterol Metabolism LXR regulates cholesterol homeostasis, crucial for maintaining lipid balance in MS LXRα, LXRβ Phagocytes, oligodendrocytes Cholesterol efflux genes (ABCA1, ABCG1), oxysterols Enhances cholesterol efflux and reduces intracellular lipid buildup Decreases lipid overload in immune cells, prevents cytotoxicity Helps manage lipid overload due to myelin degradation Potential for lipid metabolism control in MS Achieving balance between lipid clearance and cell survival is complex Anti-inflammatory and Neuroprotective Role LXRs reduce neuroinflammatory responses in CNS cells, protecting against neurodegeneration LXRα, LXRβ Microglia, astrocytes IL-1β, IL-6, NF-κB, MCP-1 Controls inflammation, preserves neuron function Downregulates inflammatory gene expression in CNS immune cells Protects against neurodegenerative damage in CNS Targeting LXRs could provide neuroprotection in MS Risk of immunosuppression with prolonged LXR activation Clinical Relevance of LXR-Mediated Pathways LXR signaling modulates myelin repair, lipid metabolism, and immune regulation, crucial for MS management LXRα, LXRβ CNS and immune cells LXR response genes, inflammatory pathways, cholesterol metabolism genes Controls multiple MS-related pathways, influencing symptoms and progression Reduces demyelination, limits inflammation, and aids in repair processes Provides a comprehensive target for MS management LXR-targeted treatments may provide multi-faceted MS benefits Requires precise targeting to avoid broad systemic effects

This table provides an in-depth overview of the mechanisms through which LXRs affect MS progression, highlighting their functions in cholesterol metabolism, inflammation suppression, and myelination, as well as their therapeutic potential in MS management

Discussion

As a novel approach to controlling complicated central nervous system disorders, the RXR and LXR signaling pathways have the ability to be therapeutic targets in MS and other neurodegenerative diseases. Their utility in creating new treatments is highlighted by the interaction between these nuclear receptors and the metabolic and inflammatory pathways. Notably, RXR has a multi-functional role in regulating physiological processes ranging from oxidative stress reduction to cholesterol efflux due to its heterodimerization with several receptors (including LXR, PPAR, and NURR1). Because of their wide variety of receptor interactions, RXR agonists are well suited to treating the various pathological aspects of MS because they influence a wide range of biological processes. An additional critical component of RXR and LXR’s function in MS is its influence on central nervous system cholesterol metabolism, specifically in myelination and myelin repair. Myelin sheaths, which encase neurons and allow them to communicate and be insulated, necessitate a high concentration of cholesterol, which the central nervous system produces from new sources. One possible strategy for repairing the damaged myelin found in MS could be to activate LXR, which promotes cholesterol efflux and myelination. Microglia are involved in cleaning myelin debris as part of myelin repair. LXR activates genes that are involved in cholesterol metabolism, which helps microglia clear debris effectively and keeps cells healthy. Accurate regulation is necessary to prevent side effects in non-targeted tissues when transforming these systems into successful medicines. Their significance in MS is further enhanced by the hereditary component of RXR and LXR signaling. As an example, changes in NR1H3, linked to LXRα, can affect the way the disease progresses in familial form of multiple sclerosis, indicating that hereditary variables can influence how the receptor works. These results suggest that genetic screening and other tailored treatment approaches could improve therapeutic outcomes by adapting therapies to each patient’s unique genetic profile. Additionally, learning about RXR and LXR polymorphisms could help in optimizing treatment options by shedding light on the diversity in patient responses to receptor-targeted medications.

The systemic roles of RXR and LXR agonists pose obstacles that must be addressed in clinical applications, despite the fact that they have great therapeutic promise. The extensive expression of RXRs and LXRs across several organs and tissues makes their broad activation a potential cause of systemic metabolic alterations or immune suppression, which could make the safety profile of these medicines more complex. The development of tailored delivery methods capable of selectively activating the RXR and LXR pathways inside the central nervous system is, hence, an area of active research. The potential for CNS-specific therapeutic advantages to be maximized while peripheral side effects are minimized using this method. In order to overcome these obstacles and enable the clinical usage of RXR/LXR-based therapeutics, advancements in nanotechnology and CNS-targeted drug delivery could be crucial. The role of RXR and LXR in conjunction with additional neuroprotective and anti-inflammatory drugs is another field of investigation. Combining RXR/LXR agonists with other medications may have a synergistic impact, especially in treating relapses or advance stages of MS, because they lower neuroinflammatory reactions. By tackling numerous pathogenic processes at once, combination therapy may improve anti-inflammatory and neuroprotective effects, offering a more all-encompassing method of treating multiple sclerosis. There is hope for the development of multimodal therapeutics that address the complex pathophysiology of MS through the ongoing research of RXR/LXR combination with other anti-inflammatory drugs. Finally, as a means to regulate inflammatory response, lipid metabolism, and the immunological response, RXR and LXR nuclear receptors show tremendous potential as MS treatment targets. Additional study is needed to create tailored techniques that reduce systemic effects, improve delivery to central nervous system tissues, and account for genetic factors in patient-specific responses, in order to fully utilize their therapeutic potential. These developments pave the way for RXR and LXR signaling pathways to play a central role in MS treatment, opening up new possibilities for the management of this difficult neurodegenerative illness.

Conclusion

The significance of nuclear receptors, particularly RXR and LXR, in the development and treatment of MS highlights the multi-faceted nature of neurodegenerative diseases’ effects on myelination, neuroinflammation, and cholesterol metabolism. Nuclear receptors have a role in the control of cellular processes that impact the development of the disease and possible treatment paths. Because of their roles in anti-inflammatory pathways and cholesterol homeostasis, LXRs and RXRs are potential targets for regulating neuroinflammatory and neurodegenerative reactions. The RXR/LXR pathways have the potential to hinder the progression of MS and aid in CNS repair processes due to their unique capacity to control gene expression associated with lipid metabolism, inflammation, and immune response. Additionally, these receptors help keep the blood–brain barrier intact and influence immune cell activity in the central nervous system, both of which mitigate the impact of neuroinflammatory insults in multiple sclerosis.

In addition to multiple sclerosis, other neurodegenerative illnesses may be amenable to the therapeutic effects of RXR and LXR agonists due to their effects on inflammation reduction, myelin regeneration, and metabolic regulation. In order to combat myelin loss and encourage remyelination in multiple sclerosis, it is crucial to understand how LXRs regulate cholesterol efflux and myelination. Similarly, RXRs are a diverse target in the therapy of neuroinflammatory diseases due to their ability to form heterodimers with other nuclear receptors. This allows them to control a broad spectrum of cellular responses. The RXR/LXR pathway’s potential in MS treatment is bolstered by its roles in oxidative stress response regulation, microglial activation reduction, and inflammatory cytokine production management. However, there are obstacles to the practical use of RXR and LXR-based therapies, such as the requirement for selective targeting of CNS cells without harmful effects on peripheral tissues. The extensive expression of RXRs and LXRs in different tissues makes this specificity all the more important, since incorrect activation could cause unwanted side effects. Also, genetic factors like NR1H3 mutations in MS families suggest that genetic profiling could improve treatment outcomes by enabling more targeted therapies tailored to each patient’s unique genetic makeup. To fully use the therapeutic potential of RXR/LXR pathways while limiting dangers associated with broad systemic activation, advancements in targeted delivery methods are necessary. Additionally, the promotion of anti-inflammatory phenotypes in immune cells is evidence that the RXR and LXR pathways contribute to immune regulation. An important symptom of MS is the infiltration of immune cells from the periphery into the central nervous system (CNS). This immune modulation has the potential to lessen this inflammatory-induced damage. Further investigation into the mechanisms by which RXR and LXR agonists can reduce neuroinflammatory responses and enhance neuroprotective activities by targeting microglia and astrocytes specifically is warranted. Further investigation into the interconnections between RXR and LXR and other receptors is encouraging, since it may lead to synergistic therapeutic results when used in conjunction with other medications for MS. To summarize, RXR and LXR regulate cholesterol levels, neuroinflammation, and immune cell activity, three distinct but related biological processes that play a part in MS management. Researchers hope that by focusing on these receptors, they can alleviate some of the many symptoms of MS, including the disease’s progressive nature, the impact on quality of life, and the frequency of relapses. It is crucial to keep investigating the mechanisms and therapeutic uses of RXR and LXR since their research shows great potential for creating sophisticated, multi-targeted treatments that deal with the inflammatory and degenerative components of multiple sclerosis.