The nutrigenomic-epigenetic axis in cancer: from dietary bioactives to precision oncology.

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Introduction

Cancer has emerged as a significant global public health challenge, currently ranking as the second leading cause of death across diverse populations worldwide [ 1 ]. According to numerous epidemiological studies, the most frequently diagnosed cancers among females include breast, colorectal, and lung cancers, whereas among males, lung, prostate, and colorectal cancers are the most prevalent [ 2 ]. Recent global estimates indicate that in 2022, approximately 20 million new cancer cases and roughly 10 million cancer deaths occurred worldwide, with an estimated 53.5 million individuals alive within 5 years of a cancer diagnosis, underscoring the substantial and continuing global burden of cancer [ 3 ]. In addition to fundamental factors that contribute to the development and progression of various forms of cancer, there exists a plethora of modifiable risk factors that can significantly influence an individual’s cancer burden, including, but not limited to, dietary choices, smoking behaviors, body mass index (BMI), and a multitude of lifestyle habits that are often within a person’s control to change [ 2 , 4 ]. Recent studies have demonstrated that several bioactive dietary compounds, including polyphenols and flavonoids (e.g., resveratrol, quercetin, and curcumin), isoflavones (e.g., genistein), isothiocyanates (e.g., sulforaphane), micronutrients (e.g., selenium), and other phytochemicals (e.g., withaferin A and indole-3-carbinol), exhibit potential chemopreventive properties that may reduce cancer risk through diverse molecular pathways. These effects are thought to be mediated, at least in part, through epigenetic mechanisms that regulate gene expression without altering the underlying DNA sequence [ 5 , 6 ]. Numerous factors related to lifestyle choices, environmental conditions, and dietary practices have been linked to improvements in cancer treatment outcomes, with the underlying mechanisms by which these elements exert their influence posited to operate, at least in part, through epigenetic modifications [ 4 ]. In the context of cancer biology, epigenetic regulation refers to heritable or stable changes in gene expression and chromatin state that occur without alteration of the underlying DNA sequence [ 7 , 8 ]. Evidence from numerous studies indicates that nutrients serve a dual role: beyond fulfilling basic metabolic and physiological needs, they also play a significant part in the prevention and therapeutic management of cancer, a debilitating and potentially fatal disease affecting millions of individuals worldwide [ 9 , 10 ]. This comprehensive review aims to provide an extensive exploration of the influence of bioactive dietary components, which interact with and affect a variety of epigenetic mechanisms, on the primary epigenetic processes involved in cancer development and progression, while synthesizing and discussing the current literature on this important topic.

Epigenetic modifications

DNA methylation

Epigenetic phenomena are widely regarded as pivotal mechanisms in the initiation and progression of various forms of cancer, as evidenced by numerous studies in the field [ 11 ]. Among the myriad of epigenetic modifications identified, DNA methylation stands out as one of the most prevalent and consequential alterations within the genomic landscape [ 12 ]. The four fundamental nitrogenous bases (adenine, thymine, cytosine, and guanine) that constitute the majority of nucleotide sequences in eukaryotic DNA are essential for maintaining the structural stability and functional integrity of the genetic material [ 13 ]. A major covalent modification of DNA is the methylation of cytosine at the carbon-5 position, producing 5-methylcytosine, which constitutes approximately 1% of total DNA bases in the human genome [ 14 ]. The transformation of cytosine into its methylated form, 5-methylcytosine (5mC), is catalyzed by a specialized group of enzymes known as DNA methyltransferases (DNMTs) [ 15 ]. In this biochemical context, S-adenosyl methionine (SAM) serves as the crucial methyl group donor utilized by DNMT enzymes to facilitate this modification. Following the methylation reaction, SAM is converted to another important compound, S-adenosylhomocysteine (SAH), which serves as a byproduct of the methylation process [ 16 , 17 ]. During DNA replication, DNA methyltransferase 1 (DNMT1) exhibits a preferential affinity for hemi-methylated DNA, as opposed to completely unmethylated DNA, which enables it to effectively preserve the original methylation patterns present in the genomic DNA of the cell through its catalytic activity. Furthermore, ubiquitin-like containing PHD and RING finger domains 1 (UHRF1) plays a critical role in recognizing hemi-methylated regions within the DNA and is fundamentally involved in maintaining established methylation patterns throughout cell division [ 14 , 18 ]. The prevalence and intensity of DNA methylation modifications that occur specifically on the cytosine residue are significantly pronounced within the context of the CpG dinucleotide, as well as in the associated regions known as CpG islands [ 19 , 20 ]. These CpG islands have been found to overlap with the promoter regions of an estimated 70% of human genes, indicating their crucial role in gene regulation [ 14 , 21 ]. In typical cellular environments, the promoter regions of genes, especially those near CpG islands, are typically unmethylated, facilitating the binding and interaction of transcription factors and other relevant proteins with the gene, thereby promoting the processes necessary for gene expression [ 14 ]. The phenomenon of DNA methylation, particularly methylation of cytosine residues in CpG dinucleotides, has profound implications for the structural and functional integrity of the genome. When hypermethylation occurs in the promoter region of a tumor suppressor gene, it can silence that gene, thereby contributing to an environment permissive for malignant cell proliferation, as observed with genetic deletions or mutations [ 22 , 23 ]. Alterations in gene methylation are critical for understanding the molecular mechanisms underlying various forms of cancer, underscoring the importance of epigenetic modifications in regulating gene expression and maintaining genomic stability. Thus, the intricate interplay between DNA methylation patterns and gene expression is a fundamental aspect of both normal cellular function and disease pathogenesis, particularly in oncogenesis [ 24 ].

Dietary modulation of miRNA expression

Significant concerns arise regarding the feasibility of directly extrapolating findings from experimental models to humans, largely because of the complexity of human dietary patterns and the difficulty of achieving physiologically relevant concentrations of bioactive compounds under typical living conditions. Epigallocatechin-gallate (EGCG), one of the predominant polyphenols in green tea, and quercetin, a major flavonoid in the human diet, have been shown to modulate the expression of numerous specific microRNAs in cultured HepG2 liver cancer cells and in murine macrophages, respectively [ 25 , 26 ]. Several studies have reported these biological effects at concentrations of 50–100 µM, which are not attainable in vivo, where circulating levels of many dietary bioactives typically remain within the low nanomolar range. This discrepancy underscores the limitations of directly extrapolating in vitro findings to clinical or real-world settings and highlights the importance of considering bioavailability, metabolism, tissue distribution, and physiologically achievable exposure when interpreting the epigenetic effects of dietary compounds. Accordingly, although these experimental observations provide valuable mechanistic insight, their translational relevance should be interpreted with caution unless supported by evidence from physiologically relevant models or human studies [ 27 ]. A critical evaluation of the literature suggests that the likelihood of achieving substantial therapeutic effects through targeted nutritional supplementation in humans is low, raising questions about the practical efficacy of such approaches. Nonetheless, extensive epidemiological evidence consistently indicates that phytochemical-rich diets are associated with a reduced risk of multiple chronic diseases. Because these conditions often involve dysregulated microRNA (miRNA) expression and function, it is plausible that phytochemicals exert subtle yet durable health effects by modulating miRNA activity [ 26 , 28 ]. These observations highlight the role of dietary phytochemicals as modulators of miRNA-mediated regulatory pathways and their potential long-term contribution to lowering chronic disease risk.

Histone modifications

Histones are specialized proteins that are intricately organized within the structural unit known as the nucleosome, which serves as a fundamental building block of chromatin [ 29 ]. Nucleosomes not only function as structural components but also as critical protectors of the genome, thereby safeguarding the delicate strands of DNA from a myriad of potentially harmful environmental factors and biological agents, while concurrently imparting significant epigenetic signals upon the DNA itself [ 30 ]. In addition to the well-documented process of DNA methylation, histone modification emerges as a crucial and sophisticated epigenetic mechanism that plays a pivotal role in gene regulation and expression [ 31 ]. The array of histone modifications encompasses a variety of biochemical alterations, including, but not limited to, lysine methylation, arginine methylation, the conversion of arginine to citrulline, lysine acetylation, and the phosphorylation of serine, threonine, and tyrosine residues. These alterations to histones trigger consequential changes in DNA transcriptional activity, thereby influencing the overall gene expression profile within the cell [ 32 ]. Histone modification is predominantly facilitated by histone tails, which serve as dynamic sites for enzymatic activity. The enzymes histone deacetylases (HDACs) and histone acetyltransferases (HATs) play a crucial role in remodeling chromatin architecture, thereby altering DNA accessibility and transcriptional potential [ 33 ]. These two classes of enzymes are functionally antagonistic, each serving distinct roles in modulating histone modifications. Specifically, the histone acetyltransferase enzyme adds acetyl groups to lysine residues on histones, a modification that neutralizes the positive charge on lysine, thereby reducing the affinity between histones and negatively charged DNA [ 34 ].

The weakening of the interaction between histones and DNA facilitates the movement of DNA away from its tightly packed state, with profound implications for the accessibility of genetic material. In contrast, histone deacetylases remove acetyl groups from histones, promoting chromatin compaction and reduced DNA accessibility, thereby contributing to transcriptional repression and, in cancer, potentially to the silencing of tumor suppressor genes [ 31 ]. The various modifications that occur to histones within chromatin are not trivial but play critical roles in regulating gene expression and processes associated with carcinogenesis, highlighting their significance in cellular biology [ 11 ]. The enzymatic activities of HAT and HDAC involve the intricate addition or removal of acetyl groups from non-histone proteins, which subsequently lead to substantial changes in the cellular environment and influence various cellular outcomes [ 35 ]. Furthermore, this is important to note that histone deacetylase enzymes are classified into four distinct categories, each exhibiting unique mechanisms and functional roles within the cell. Histone deacetylases are classified into four major classes. Classes I, II, and IV include the classical zinc-dependent HDACs (HDAC1–HDAC11), whereas Class III comprises the NAD+-dependent sirtuins (SIRT1–SIRT7), which differ in both catalytic mechanism and biological function [ 36 , 37 ].

Non-coding RNAs (ncRNAs)

miRNAs regulate gene expression at the post-transcriptional level by binding target messenger RNAs, thereby promotingmRNA degradation or translational repression and refining gene-expression programs [ 19 ]. While DNA methylation and histone modification are among the most extensively studied domains of mechanisms governing gene expression, the impact of dietary components on miRNAs has emerged as a significant focus of scholarly inquiry [ 38 ]. Specific miRNAs are small, non-coding RNA molecules that act as essential post-transcriptional regulators of gene expression. By binding to complementary sequences on target messenger RNAs, miRNAs regulate a substantial proportion of protein-coding genes and thereby influence key cellular processes such as proliferation, differentiation, and apoptosis. Aberrant miRNA expression disrupts these regulatory networks and has been strongly implicated in the initiation and progression of cancer [ 39 ].

Chromatin remodeling

Chromatin is a nucleoprotein complex that structurally organizes and functionally regulates DNA, thereby facilitating various cellular processes, including gene transcription, cellular division, differentiation, and DNA repair [ 40 ]. In eukaryotic organisms, the nucleosome is the fundamental unit of chromatin, comprising a histone octamer and 147 base pairs of DNA. The core histone proteins of the nucleosome (H2A, H2B, H3, and H4) [ 41 ] are prominent targets for covalent post-translational modifications (PTMs), which are dynamically regulated by specialized enzymes that modify histones [ 42 ]. PTMs significantly influence chromatin structure, play a pivotal role in chromatin remodeling, and ultimately alter DNA function. Furthermore, these modifications facilitate the recruitment of remodeling enzymes that harness the energy released from ATP hydrolysis to reposition nucleosomes effectively [ 43 , 44 ]. The recruitment of proteins and complexes endowed with specific enzymatic functions has now been widely recognized as a fundamental principle governing chromatin functionality [ 42 ]. In the context of gene transcription regulation, chromatin remodeling facilitates the dynamic reconfiguration of DNA from a more compacted form, referred to as heterochromatin (transcriptionally inactive), to a transcriptionally permissive configuration (euchromatin); the latter permits the intricate apparatus of DNA-binding proteins and transcription factors to engage with DNA, thereby modulating gene expression [ 45 , 46 ]. Histones frequently harbor numerous post-translational modification sites that can interact and influence one another, thereby orchestrating a more intricate transcriptional response to various stimuli. Owing to this property, chromatin modifications (similar to other forms of epigenetic alterations) are reversible and, consequently, adjust chromatin architecture to enhance gene activation or repression in response to both extracellular and intracellular signals [ 47 ]. Table 1 provides an overview of the major epigenetic mechanisms implicated in oncogenesis.

Epigenetic dysregulation in cancer

Aberrant epigenetic changes in hematologic malignancies

Findings suggest that dysregulation of DNMT activity, in conjunction with DNA hypermethylation specifically observed in leukemic stem cells (LSCs), plays a significant role in the complex process of leukemogenesis [ 48 ]. For instance, conditional knockout of the DNMT1 gene has been shown to effectively halt the progression of leukemia, while its haploinsufficiency has been shown to significantly delay the progression of leukemogenic processes and adversely affect the self-renewal capacity of LSCs, all without a detrimental impact on normal hematopoietic function [ 49 ]. This implies that LSCs are critically dependent on silencing bivalent domains via DNA methylation to maintain the repression of key genes. Furthermore, activating mutations within the DNMT3A gene, which is typically expressed in embryonic and progenitor cells, have emerged as significant indicators of poor prognostic outcomes in AML. These mutations are found to correlate with intermediate-risk profiles and with other leukemogenic mutations affecting genes such as FLT3-ITD, NPM1 , PTPN11 , and IDH2 [ 50 ]. Mutations in the DNMT3A gene are identified in approximately 22.9% of patients with AML and normal karyotype, as reported in previous studies [ 50 ]. These mutations have the potential to enhance risk stratification in AML, thereby enabling more tailored therapeutic approaches [ 51 ].

Furthermore, the overall survival rates for patients who achieve complete remission are significantly prolonged in cases without DNMT3A mutations, whereas those individuals harboring mutations in this gene tend to experience a markedly elevated rate of relapse following treatment [ 50 , 51 ]. Notably, DNMT3A mutations are infrequently found in pediatric cases of myelodysplastic syndromes (MDS) and acute myeloid leukemia, as well as in juvenile myelomonocytic leukemia, in stark contrast to their prevalence in adult populations [ 52 ]. This discrepancy suggests that mutations in this gene may be influenced by patient age, although the underlying biological mechanisms responsible for this variation and its subsequent clinical ramifications remain largely elusive [ 53 , 54 ]. Delving into the intricacies of such age-related differences could significantly enhance our comprehension of the pathological mechanisms underlying leukemia, thereby paving the way for improved therapeutic outcomes for affected children. Many key transcriptional modulators (KTMs) implicated in the intricate process of hematopoiesis have been shown to play crucial roles in the complex mechanisms underlying leukemogenesis, the pathological process leading to leukemia [ 55 ]. For instance, the proteins Suv39h1 and Suv39h2 have been identified as mediators facilitating the direct trimethylation of histone H3 at lysine 9 (H3K9) specifically within the pericentric regions of heterochromatin. This modification contributes to the immortalization of bone marrow cells, a phenomenon that has been extensively discussed in recent literature [ 56 ]. Inhibition of Suv39h1 has been shown to re-express tumor suppressor genes previously silenced by epigenetic mechanisms in AML cells, suggesting significant therapeutic potential [ 57 ]. Across various leukemia subtypes, the fusion oncogene PML-RARα has been observed to interact with the Polycomb Repressive Complex 2 (PRC2), directing it toward specific target genes. Furthermore, the knockdown of SUZ12, a critical component of the PRC2 complex, has been demonstrated to induce granulocytic differentiation in cells derived from acute promyelocytic leukemia (APL) [ 58 ]. Similarly, the PRC1 member B-lymphoma Mo-MLV Insertion Region 1 (BMI1) has been recognized for its pivotal role in leukemogenesis, as evidenced by studies in both murine and human cell models [ 59 ]. BMI1 has also been found to facilitate the reprogramming of chronic myeloid leukemia (CML) B-lymphoid progenitors, transforming them into cells that initiate B-cell acute lymphoblastic leukemia (B-ALL) [ 60 ]. Moreover, the fusion protein NUP98–NSD1, prominently associated with AML, functions as an active histone 3 lysine 36 methyltransferase [ 61 ], while the multiple myeloma-specific SET domain, known as NSD2 or MMSET , serves as a critical methyltransferase involved in the t(4;14) (p16;q32) chromosomal translocation, frequently observed in multiple myeloma (MM) and notably correlated with a poor clinical prognosis [ 62 ]. The MMSET (NSD2) has been shown to significantly alter global histone methylation patterns [ 63 ] and to recruit histone deacetylases 1 and 2 (HDAC1 and HDAC2) in the cellular context of t(4;14)-positive multiple myeloma cells [ 64 ]. This recruitment ultimately results in persistent and abnormal DNA hypermethylation states that can have deleterious effects on gene expression. Furthermore, the overexpression of various histone deacetylases, specifically HDAC1, HDAC2, HDAC3, HDAC6, HDAC7, and HDAC9, has been identified in a multitude of leukemic conditions, including chronic lymphocytic leukemia (CLL), where these enzymes play a pivotal role in contributing to the pathogenesis and progression of the disease [ 65 , 66 ]. A distinct expression pattern of Polycomb Group (PcG) proteins (including BMI1, MEL18, RING1A/B, PH1, HPC1, EED, and zeste homolog 2 [EZH2]) has been reported in Hodgkin’s lymphoma. This coordinated dysregulation highlights a potential therapeutic opportunity to selectively target malignant cells in this disease. It also raises the question of whether comparable histone-modification signatures occur in other cancers and could similarly elucidate pathogenic mechanisms. The PcG-related alterations observed in Hodgkin’s lymphoma appear to hold notable clinical significance. For example, reduced or aberrant expression of RYBP , a component of RING1A/B -containing complexes, has been associated with poorer survival, suggesting its potential utility as a prognostic biomarker [ 67 ].

Moreover, aberrant DNA hypermethylation has been implicated in leukemogenesis, primarily by silencing critical tumor suppressor genes that otherwise inhibit malignant transformation. For instance, inactivating mutations of the IDH2 gene, which are known to be leukemogenic, have been correlated with both DNA and histone hypermethylation in AML [ 68 ]. The DNA hypermethylation, with significant implications for the pathogenesis of various cancers, may be perpetuated and orchestrated by aberrantly activated PcG proteins in cancer cells. These specific lysine-targeting methyltransferases exert their influence by directly inducing histone methylation while simultaneously facilitating DNA hypermethylation and histone deacetylation indirectly through the strategic recruitment of DNMT1 [ 69 , 70 ] and HDAC1/2 [ 71 ]. As observed in stem and progenitor cells [ 72 ], numerous tumor suppressor genes adversely influenced by PcG proteins, including WT1 , RARβ , KLF4 , ID4 , GATA3 , CHD5 , and SPI1 , show marked accumulation of DNA methylation at their promoter regions specifically within cancer cells [ 73 ]. This phenomenon is not merely an isolated occurrence; it is prevalent across various hematological malignancies, including, but not limited to, ALL and CML, as well as diffuse large B-cell lymphoma, follicular lymphoma, and Burkitt lymphoma [ 74 , 75 ]. This prevalence suggests that these mutations are ubiquitous within the spectrum of hematological disorders. The implications of these findings suggest that pharmacological interventions targeting these epigenetic modifications may yield therapeutic benefits. Notably, the development and clinical approval of DNA methyltransferase inhibitors (DNMTi), such as decitabine (5-aza-2′-deoxycytidine) and 5-azacytidine, have emerged as promising treatment options for conditions such as MDS, CML, and AML [ 76 , 77 ]. Furthermore, additional DNMT inhibitors are currently undergoing evaluation in clinical trials [ 78 , 79 ]. A review of current oncologic therapies underscores the central role of DNA hypomethylating agents, which are designed to restore the expression of tumor suppressor genes silenced by aberrant hypermethylation. These agents primarily inhibit key epigenetic regulators, including DNMTs, lysine methyltransferases (KMTs), and HDAC, thereby modulating chromatin structure and transcriptional activity. Decitabine, for example, is used in high-risk myelodysplastic syndrome patients who are ineligible for hematopoietic stem cell transplantation and has been shown to reduce global methylation in acute myeloid leukemia cells, leading to improved response rates compared with conventional therapies [ 76 , 77 ]. This drug exerts its anti-cancer effects by inducing apoptosis in AML cells through the generation of intracellular reactive oxygen species, which serve as critical mediators of cellular stress and death. However, it is important to acknowledge that decitabine is not without its drawbacks, as it is associated with significant adverse effects, including pronounced bone marrow toxicity [ 80 , 81 ]. This particular complication has been somewhat mitigated by administering low doses of the pharmacological agent in combination with conventional anticancer agents, representing a more efficacious therapeutic strategy than monochemotherapy, especially in the context of chemoresistant malignancies [ 76 , 81 ]. Furthermore, the KTM inhibitor (KTMi) chaetocin, which inhibits Suv39h1 and G9a , has been shown to effectively impede the hypermethylation of tumor suppressor genes in AML cellular contexts and to exhibit antimyeloma properties by inducing oxidative stress in MM cells [ 82 ]. Additionally, various histone deacetylase inhibitors (HDACi) have been synthesized, several of which are currently utilized in oncological treatment regimens. Notably, innovative HDACi exhibiting significant antileukemic efficacy in myeloid cell cultures and primary AML blasts at low micromolar concentrations have recently been introduced [ 83 ]. Recent investigations into childhood B-ALL have indicated that epigenetic reprogramming can counteract gene expression signatures associated with relapse while simultaneously reinstating chemosensitivity, as evidenced by numerous scholarly articles [ 84 ]. These studies demonstrate that combining the histone deacetylase inhibitor Vorinostat with the hypomethylating agent decitabine reprograms the aberrant gene-expression profiles characteristic of relapsed leukemic blasts. Decitabine alone can restore the expression of genes preferentially methylated at relapse in both primary patient samples and leukemia cell lines, yet the dual regimen yields substantially greater therapeutic activity than either agent administered individually. These findings indicate that multiple epigenetic pathways act cooperatively to promote chemoresistance during relapse. Similar observations in aggressive, drug-resistant metastatic solid tumors underscore the broader relevance of epigenetic reprogramming strategies across diverse malignancies [ 85 ]. Intriguingly, HDACi have been shown to enhance the anticancer efficacy of conventional chemotherapeutic agents, emphasizing the importance of integrating these compounds into established treatment regimens. An expanding body of experimental evidence further indicates that DNA hypermethylation, frequently linked to the overexpression of PcG proteins, can also arise from the silencing or complete loss of diverse PcG regulatory elements. Among these elements, miRNAs have emerged as critical contributors that are often silenced in malignant contexts, as the downregulation of specific miRNAs is a defining feature of several cancer types, including t(14;18)-negative follicular lymphoma and Burkitt lymphoma [ 86 – 88 ]. MicroRNAs such as miR-137 and miR-214 play key roles in regulating cancer cell differentiation by modulating EZH2 levels, a protein essential to multiple cellular processes. Downregulation of specific microRNAs, including miR-200c, miR-203, and miR-183, has also been shown to promote BMI1 expression in mouse embryonic stem cells and various cancer cell lines, thereby contributing significantly to the maintenance of stemness in these cell populations. Consistent with these findings, recent advances in non-coding RNA–based therapeutic strategies aim to inhibit the translation of DNMTs activated by mutations, representing a promising direction for future cancer treatment modalities [ 89 – 91 ].

Despite numerous preliminary investigations demonstrating their involvement in solid tumors such as ovarian cancer and in hematological malignancies, including AML, substantial gaps remain in our understanding of the functions of DNA demethylases and DNA glycosylases. These enzymes are key contributors to DNA demethylation, particularly in hematological malignancies. Recent literature further shows that a central component of the DNA base excision repair pathway, 8-oxoguanine glycosylase ( OGG1 ), which removes 8-oxoguanine nucleotides from DNA to limit mutagenesis and protect cells from apoptosis, is markedly downregulated by the RUNX1-ETO leukemia fusion protein. This downregulation has been documented in both normal hematopoietic progenitor cells and samples from patients with AML [ 92 – 94 ]. A comprehensive investigation focusing on the OGG1 gene polymorphism has yielded findings indicating that certain alleles, particularly the R229Q variant, may serve as significant predictors of heightened cellular vulnerability to malignant transformation, a phenomenon previously documented [ 92 ]. The polymorphic nature of this enzyme has also been associated with an increased risk of AML, particularly in pediatric populations [ 95 ]. Recent studies have also identified additional mechanisms that facilitate DNA demethylation, including histone demethylation mediated by lysine demethylases (KDMs) and histone acetylation catalyzed by histone acetyltransferases (HATs). These processes are integral to the development and maintenance of LSCs [ 96 , 97 ]. Recent studies proposed that the H3K9 demethylase KDM3B actively suppresses leukemia cell differentiation, a finding of particular relevance given that KDM3B is upregulated in the blood cells of patients with ALL. KDM3B exhibits demethylase activity toward mono- and dimethylated histone H3K9 and contributes to the upregulation of the leukemogenic oncogene lmo2 through interdependent interactions with HATs, highlighting the complexity of epigenetic regulation in leukemogenesis [ 98 ]. KDM3B is further reported to undergo marked downregulation during all-trans-retinoic acid (ATRA)–induced differentiation in HL-60 APL cells, illustrating the dynamic transcriptional changes associated with cellular maturation [ 99 ]. Recent studies have also identified inactivating mutations in several components of the PRC2 complex, including EZH2 , SUZ12 , EED , and Jarid2 , which have been implicated in multiple myeloid neoplasms. These findings suggest a potential mechanism of tumorigenesis driven by epigenetic dysregulation [ 100 ]. Additionally, the HAT activity of the enzyme MOZ has been shown to facilitate the generation of fusion genes when it interacts with other HAT proteins, such as CBP and p300, in the context of AML. The resultant fusion proteins, emerging from this complex interplay, are implicated in the pathological processes that lead to the repression of normal differentiation pathways, increased hyperproliferation, and the promotion of self-renewal in transforming myeloid progenitor cells, ultimately contributing to the malignancy observed in this hematological disorder [ 101 ]. DNA hypomethylation is also closely associated with the aberrant overexpression of the oncogenic transcription factor Myc, a phenomenon observed across multiple lymphoma types, in which this factor’s dysregulation contributes substantially to disease pathogenesis and progression [ 102 ]. Analogous to numerous solid tumors, a widespread reduction in the methylation levels of repetitive genomic sequences, including long interspersed nuclear element 1 (commonly referred to as LINE-1), Alu sequences, and satellite alpha (SAT-alpha) sequences, has been correlated with the phenomenon of chromosomal instability, particularly observed in CLL and multiple myeloma (MM) [ 103 , 104 ]. Although early studies proposed this marker as an independent prognostic indicator strongly associated with reduced therapy-free survival, subsequent investigations in malignancies demonstrated that global hypomethylation of repetitive DNA elements is closely linked to tumor progression and contributes to more robust molecular stratification. These observations indicate that DNA hypomethylation, occurring not only at promoter regions but also across multiple genomic compartments, is integral to the mechanisms driving the pathogenesis of hematological malignancies. Future research may therefore identify novel pharmacological targets that could support the development of more effective therapeutic approaches. Within this context, epigenetic regulators that modulate chromatin architecture represent particularly promising targets, given the reversible nature of histone modifications and their suitability for targeted intervention. Advancing this line of inquiry has the potential to deepen our understanding of disease biology and facilitate the development of innovative therapeutic strategies that leverage chromatin plasticity. Continued scientific investment in this area remains essential, as the potential impact on patient management and clinical outcomes is considerable [ 105 , 106 ].

In anticancer therapeutic development, DNA hypomethylating agents have attracted considerable interest because they can restore the expression of tumor suppressor genes silenced by aberrant promoter hypermethylation. In parallel, additional epigenetic strategies have been developed to target histone-modifying enzymes, including KMTs, HDACs, and other chromatin regulators involved in malignant transcriptional reprogramming [ 107 , 108 ]. These agents aim to suppress oncogenes aberrantly activated through DNA hypomethylation, a hallmark of malignant cells that contributes to tumor progression. Building on these advances, considerable efforts are now underway to develop highly specific inhibitors of lysine demethylases (KDMi), which play essential roles in regulating cellular methylation states. Recent research has focused on selectively targeting the JmjC catalytic domain, which is essential for KDM demethylase activity yielding promising mechanistic insights. Compounds such as disulfiram and ebselen have been shown to inhibit JmjD2A by disrupting its structural zinc-binding site, thereby impairing enzyme function and highlighting a potential mechanism for pharmacologic interference with histone demethylase activity [ 109 ]. LSD1, or lysine-specific histone demethylase 1, exhibits considerable homology at its catalytic site with flavin-dependent amine oxidases (MAO), a class of enzymes widely targeted in the treatment of neurological disorders. Notably, MAO inhibitors such as tranylcypromine and phenelzine have been found to inhibit LSD1 activity, suggesting a pharmacological intersection with potential implications for neurological disease management [ 110 ]. In AML, LSD1 inhibition has been shown to restore activation of the ATRA differentiation pathway, highlighting its therapeutic relevance in this malignancy [ 111 ]. Figure 1 illustrates the shift from physiologic epigenetic regulation to the dysregulated patterns characteristic of cancer.

Epigenetic alterations in solid tumors

Aberrant epigenetic alterations are fundamental to the initiation and progression of solid tumors, where they contribute to intratumoral heterogeneity, lineage plasticity, metastatic potential, and therapeutic resistance. In contrast to the comparatively narrower discussion often applied to hematologic malignancies, solid tumors demonstrate a more complex and extensive interplay among focal promoter hypermethylation, global DNA hypomethylation, dysregulated histone modifications, and defects in chromatin-remodeling machinery [ 112 , 113 ]. Contemporary evidence indicates that these abnormalities are not merely secondary or passenger events, but functionally significant mechanisms that reprogram transcriptional networks, suppress tumor suppressor pathways, and facilitate malignant adaptation across a broad spectrum of epithelial malignancies, including breast, lung, colorectal, ovarian, prostate, and hepatocellular cancers [ 114 – 116 ].

Among these epigenetic abnormalities, promoter CpG island hypermethylation remains one of the most consistent and well-characterized features of solid tumors [ 117 , 118 ]. Hypermethylation-mediated silencing of tumor suppressor genes has been documented in several common malignancies, including colorectal, lung, prostate, breast, and ovarian cancers, and may involve genes regulating cell-cycle progression, DNA repair, cell adhesion, apoptosis, and therapeutic responsiveness. Representative examples include aberrant methylation of CDKN2A, CDH1, APC, RASSF1, and BRCA1, depending on the tumor type and biological context. In ovarian cancer, in particular, DNA methylation alterations have also been implicated in platinum resistance, further supporting the concept that epigenetic dysregulation contributes not only to tumor initiation and progression but also to treatment failure and disease persistence [ 119 – 121 ].

In parallel, solid tumors are frequently characterized by widespread global hypomethylation, particularly within repetitive genomic regions such as LINE-1 elements, a phenomenon strongly associated with chromosomal instability and aggressive tumor behavior [ 121 , 122 ]. Recent mechanistic studies have demonstrated that LINE-1 activation can directly induce DNA double-strand breaks, copy-number variation, and chromosomal rearrangements, thereby providing a plausible biological link between epigenetic deregulation and structural genomic damage. From a clinical perspective, LINE-1 hypomethylation has been associated with unfavorable outcomes in several solid malignancies, supporting its potential role as a biomarker of disease progression and prognosis. These findings indicate that epigenetic dysregulation in solid tumors occurs at both locus-specific and genome-wide levels, concurrently promoting tumor suppressor gene silencing and genomic instability [ 123 – 125 ].

Altered histone regulation and defects in chromatin-remodeling complexes constitute another major dimension of epigenetic disruption in solid tumors [ 126 ]. Overexpression or hyperactivity of EZH2, aberrant HDAC signaling, and mutations involving SWI/SNF complex components such as ARID1A, SMARCA4, PBRM1, and SMARCB1 have been reported across a wide range of solid cancers and are increasingly recognized as both biologically consequential and therapeutically relevant [ 127 – 129 ]. Notably, SWI/SNF-related abnormalities are present in a substantial proportion of solid tumors, and loss of ARID1A has been linked not only to tumor progression but also to targetable vulnerabilities that may be exploited through synthetic-lethal approaches. The translational significance of this paradigm is exemplified by tazemetostat, an EZH2 inhibitor approved by the US Food and Drug Administration for advanced epithelioid sarcoma, representing a landmark example of epigenetic precision therapy in a solid malignancy. Nevertheless, recent evidence also suggests that, outside selected molecularly defined contexts, epigenetic monotherapy in solid tumors has yielded inconsistent efficacy, and current advances are increasingly being driven by rational combination strategies involving chemotherapy, targeted therapies, radiotherapy, and immunotherapy [ 130 – 132 ].

An integrative view of solid tumors supports the concept that epigenetic dysregulation is a fundamental hallmark of cancer biology. Alterations in DNA methylation, histone-modifying enzymes, and chromatin-remodeling complexes interact dynamically to maintain oncogenic transcriptional programs and influence therapeutic response. This broader perspective is consistent with current evidence, which increasingly identifies epigenetic alterations in solid tumors as clinically relevant biomarkers and promising therapeutic targets [ 114 , 115 , 133 ].

DNA methylation in cancers: development, progression, and metastasis

DNA cytosine methylation is one of the most extensively characterized epigenetic modifications and is frequently associated with transcriptional silencing, as documented in numerous studies [ 134 ]. Altered DNA methylation patterns, particularly within CpG islands at specific gene loci, can profoundly influence tumor progression, underscoring the close interplay between epigenetic regulation and cancer biology. Several oncogenes exhibit elevated expression as a direct consequence of promoter hypomethylation, representing a key mechanism underlying cellular dysregulation [ 135 ]. In contrast, tumor suppressor genes are often transcriptionally silenced through DNA hypermethylation, as exemplified by the VHL gene in clear cell renal cell carcinoma (ccRCC) and the p16 gene in various lung cancers [ 136 ]. Beyond its effects on gene expression, DNA methylation critically modulates metastatic processes by silencing genes that inhibit dissemination. For example, hypermethylation of the 5′ CpG island of the E-cadherin gene has been identified in metastatic breast cancer, demonstrating the role of epigenetic alterations in tumor spread [ 137 ]. In ccRCC, demethylation of the serum amyloid A (SAA) genes has been shown to promote neutrophil-dependent metastatic progression, further linking methylation dynamics to metastatic phenotypes [ 138 ].

Findings establish that DNA methylation is a major driver across multiple phases of cancer development, a conclusion supported by prior reviews [ 139 ]. Assessing and profiling DNA methylation patterns have emerged as powerful analytical tools that enhance diagnostic precision in oncology. In a comprehensive study, Orizco et al. profiled the DNA methylome of brain metastases (BM) arising from melanoma, breast cancer, and lung carcinoma. Their analyses demonstrated that the methylation patterns of BM differ markedly from those of primary central nervous system tumors and that BM derived from different primary cancers exhibit distinct and characteristic methylation signatures [ 140 ]. These findings indicate that the complex methylation landscape of BM serves as a valuable biomarker for determining the tissue of origin, thereby improving diagnostic algorithms and informing therapeutic decision-making. Genome-wide methylome profiling can also be applied to patient plasma or circulating tumor cells obtained through liquid biopsy [ 141 , 142 ]. The use of these advanced methodologies, offering a deeper understanding of epigenomic alterations during the transition from primary tumor formation to metastatic spread, may significantly enhance diagnostic performance and outcome prediction while remaining minimally invasive. Figure 2 depicts contrasting patterns of DNA methylation in healthy cells versus malignant cells.

Hypoxia-driven epigenetic and transcriptional reprogramming in cancer

In the complex process of cancer progression, tumor hypoxia provides a compelling illustration of the mechanisms through which epigenetic reprogramming occurs within the malignant microenvironment. This hypoxic state arises from the inherent limitations of oxygen diffusion, particularly in avascular primary tumors or their metastatic counterparts, leading to the development of hypoxia within solid tumors [ 143 ]. This persistent hypoxic state substantially reduces the efficacy of both radiation therapy and chemotherapy, resulting in unfavorable clinical outcomes for patients with cancer. The diminished therapeutic response is largely attributable to the upregulation of prosurvival genes that inhibit apoptosis, including c-myc , AMPK, GLUT1, and BNIP3 . Activation of these prosurvival pathways also promotes tumor angiogenesis and drives key processes such as epithelial-to-mesenchymal transition (EMT), increased invasiveness, and metastatic potential, thereby exacerbating malignancy [ 144 – 149 ]. Extensive investigations into the transcriptional targets of hypoxia-inducible factors (HIFs) have underscored the central role of oxygen deprivation in cancer biology. HIF-1 functions as a heterodimeric transcription factor composed of an oxygen-regulated α subunit (HIF-1α or HIF-2α) and a constitutively expressed β subunit (HIF-1β), reflecting the complexity of its regulatory architecture. HIF-1α serves as an oxygen-responsive transcription factor that mediates cellular adaptation to hypoxic stress, a role consistently emphasized in tumor-focused studies. Under hypoxic conditions, HIF-1α becomes stabilized and translocates to the nucleus, where it dimerizes with HIF-1β at hypoxia response elements (HREs) to activate the transcription of specific target genes, a process well documented across multiple investigations [ 150 – 152 ]. The HIF-1 transcriptional activator complex is essential for regulating erythropoietin and numerous other hypoxia-responsive genes. It is composed of two subunits: HIF-1β/ARNT (aryl hydrocarbon receptor nuclear translocator), which is constitutively expressed at steady levels, and HIF-1α, which is undetectable under normoxic conditions but markedly induced during hypoxia. Under normoxia, HIF-1α is continuously synthesized and rapidly degraded; however, during hypoxia, it accumulates quickly, reflecting an immediate and robust cellular response to reduced oxygen availability [ 153 ]. HIF-1α regulates hundreds of genes involved in key biological processes, including tumor angiogenesis, cellular invasion, glycolytic metabolism, and overall cell survival. Its activation under hypoxia leads to significant alterations in cellular function, reinforcing its critical role in adaptation to low oxygen levels [ 154 ].

Hypoxia not only activates gene expression but also represses specific genes, thereby reshaping the cellular transcriptional landscape. Several genes are downregulated under low-oxygen conditions through the recruitment of repressive factors such as DEC1 and Snail, which actively mediate transcriptional repression during hypoxia. This dual capacity of HIF-1 to function as both an activator and a repressor underscores its regulatory complexity and central role in coordinating cellular responses to fluctuating oxygen levels. Consequently, hypoxia profoundly affects cellular behavior and gene regulation, positioning HIF-1 as a key focus in studies of diverse pathophysiological states, including cancer. The intricate interplay between HIF-1 and its target genes highlights the fundamental importance of oxygen sensing in cellular adaptation and survival during oxygen deprivation [ 155 ]. Under conditions characterized by a deficiency of oxygen, commonly referred to as hypoxic conditions, extensive research has demonstrated a significant upregulation in the expression levels of two important proteins, G9a and EZH2 , which subsequently results in a global increase in the hypermethylation of histone H3 at lysine 9 (H3K9) and at lysine 27 (H3K27), respectively [ 143 ]. The hypoxic environment has been associated with an elevation in repressive epigenetic modifications in the promoter regions of critical tumor suppressor genes, including, but not limited to, RUNX3 and MLH1 . This correlation has been shown to strongly associate with the silencing of these genes, thereby potentially facilitating tumor progression [ 156 , 157 ]. In tumors, G9a activity is deregulated, and under hypoxic conditions, the methylation of non-histone proteins such as Reptin can either positively or negatively influence the transcriptional activity of a specific subset of genes integral to tumor metastasis [ 158 , 159 ]. Noteworthy examples of genes modulated by the action of Reptin include, but are not limited to, Vascular Endothelial Growth Factor (VEGF), Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3), and Phosphoglycerate Kinase 1 (PGK1) [ 160 ]. Table 2 summarizes the key epigenetic abnormalities identified in major cancer types along with their clinical implications.

Mechanisms of epigenetic modification and regulation

DNA and RNA methylation

The hypermethylation of the Ulk2 gene, which is essential for autophagy initiation, leads to significant downregulation of Ulk2 , thereby disrupting autophagy, particularly during the pathophysiological progression of glioblastoma [ 161 ]. The hypermethylation of the ATG2B gene, which plays a critical role in the nucleation of vesicles required for proper autophagy, has been implicated in promoting aggressive growth in invasive breast cancer and ductal carcinomas, demonstrating a clear link between epigenetic alterations and cancer progression. Hypermethylation has also been documented in ATG4D , a gene essential to the regulatory mechanisms governing the ATG8/LC3 system, as well as in orthologs of ATG9 , both of which have been associated with the aggressive phenotype of invasive ductal carcinomas [ 162 , 163 ]. Moreover, hypermethylation affecting the promoter region of the ATG5 gene, which is known to form a critical complex with ATG12 and ATG16 during the autophagic process, results in its downregulation and contributes to the proliferation of melanoma, thus underscoring the importance of epigenetic changes in the context of tumorigenesis [ 162 , 164 , 165 ]. Hypermethylation of the promoters of several autophagy regulatory elements, which function as tumor suppressors, has been shown to contribute substantially to cancer development. For example, hypermethylation of the Beclin1 gene ( Atg6 ), a key mediator of isolation membrane initiation, leads to decreased expression in breast cancer cells [ 166 , 167 ].

Methylation of the LC3 gene, specifically MAP1LC3Av1 , results in its silencing and effectively inhibits autophagy in both normal and neoplastic gastric mucosal tissues, indicating a critical disruption in cellular homeostasis [ 168 ]. The silencing of specific genes can occur through methylation at their promoter regions; interestingly, the subsequent restoration of these methylated genes has been found to significantly enhance the formation of autophagic vacuoles, which are essential cellular structures involved in the degradation and recycling of cellular components, alongside an upregulation of key autophagy-related proteins such as Atg-5, Atg12, and LC3B II [ 169 ]. In human non-small cell lung cancer (NSCLC) cells, overexpression of the tumor suppressor candidate 3 ( TUSC3 ) has been attributed to its methylation, a modification that inhibits cellular proliferation by inducing autophagy and activating apoptosis, underscoring its critical role in cancer biology [ 170 ].

Another noteworthy gene is Aplasia Ras homolog member I ( ARHI ), which functions as a maternally imprinted tumor suppressor gene. Upon loss of its functional capacity and hypermethylation of CpG promoter elements, it becomes overexpressed and is closely associated with the progression of breast and ovarian tumors through the induction of autophagy. This illustrates the intricate relationship between epigenetic modifications and tumorigenesis [ 171 ]. The process of promoter methylation affecting B-cell translocation genes, specifically BTG1 and BTG3 in gastric cancer and BTG1 in colorectal cancer, is a significant factor contributing to the manifestation of aggressive, malignant cancer growth, which is particularly concerning for patient outcomes. However, it is imperative to note that, despite this detrimental effect, the BTG family of genes possesses tumor-suppressive properties when overexpressed, as they inhibit critical processes [ 172 – 174 ].

B-cell lymphoma 2–like protein 10 (BCLB), the most recently identified and least extensively studied member of the Bcl-2 family, plays a critical role in regulating both autophagy and apoptosis by functioning as a sensor of starvation-induced stress. Its expression is markedly repressed in hepatocellular carcinoma (HCC) due to promoter hypermethylation [ 175 ]. Additionally, the level of aggressiveness and the stage of cancer progression are intricately linked to promoter methylation of transcription factor 21 (TCF21), which is particularly relevant in NSCLC, as it leads to significant inhibition of autophagic processes that are vital for cellular homeostasis and survival [ 176 ]. Reduced activity of the enzyme nicotinamide N-methyl transferase (NNMT) has been linked to the onset of liver carcinogenesis, a process that arises primarily during periods of metabolite depletion. This depletion is associated with dephosphorylation of p-ULK1 activity and a concurrent increase in PP2A methylation, ultimately enhancing a pro-survival form of autophagy that can contribute to tumor development [ 177 ]. Regulation of autophagy in cancer is further influenced by methylation of key metabolic enzymes, including CpG island methylation of genes encoding argininosuccinate synthetase (ASS1) and argininosuccinate lyase (ASL) in glioblastomas, indicating a complex interplay between metabolic pathways and epigenetic modifications. A pro-survival autophagic response can be initiated by exposure to PEGylated arginine deiminase (ADI-PEG20), which alters the cellular environment; however, this response can subsequently be inhibited by chloroquine, a treatment that increases cytotoxicity and enhances therapeutic effectiveness [ 178 ].

Hypomethylation and demethylation processes contribute significantly to tumor progression by altering regulatory DNA regions essential for gene expression and cellular function. In lung adenocarcinoma, aberrant demethylation of the LC3A gene can initiate a pro-survival form of autophagy, illustrating the intricate relationship between epigenetic modification and tumor biology [ 179 ]. The unfavorable prognosis associated with ovarian tumor-initiating cells (OTICs) has been closely linked to hypomethylation of genes such as ATG4A and members of the histone cluster 1 H2B family, whereas increased methylation of these genes correlates with improved patient outcomes [ 180 ]. However, DNA methylation can also suppress oncogenic potential within regulatory regions of autophagy-related genes. Increased methylation of EPAS1 and ATG16L1 reduces medulloblastoma cell proliferation, an effect attributed to repression of the oncogenic hypoxia-inducible factor 1-alpha in this tumor type [ 181 ]. This relationship underscores the importance of characterizing the epigenetic landscape of cancer, particularly in understanding how methylation can either promote or inhibit tumorigenic processes.

Numerous miRNAs that modulate autophagy have also been identified as possessing growth-inhibitory properties in cancer cells. An illustrative example is observed in breast cancer cells, where the tumor-suppressive effects of miR-101 arise from its ability to repress both basal and rapamycin-induced autophagy. This activity is mediated through its regulation of key autophagy-related proteins, including RAB5A, STMN1, and ATG4D, as documented in previous studies [ 182 ]. miR-372 also exhibits tumor-suppressive activity by downregulating ULK1 expression and inhibiting autophagy in human pancreatic adenocarcinomas, establishing its potential as a therapeutic target [ 183 ]. In CLL, miR-130a acts as a negative regulator by reducing ATG2B and DICER1 expression, suppressing autophagosome formation, and promoting apoptotic cell death, highlighting the importance of microRNAs in maintaining cellular homeostasis and restraining tumor progression [ 184 ]. miR-204, regulated by the von Hippel–Lindau tumor suppressor protein, has been extensively characterized for its ability to inhibit cancer cell proliferation by blocking LC3B-mediated autophagy in renal clear cell carcinoma [ 185 ]. miR-375 has also been shown to impair the viability of hepatocellular carcinoma cells under hypoxic conditions by inhibiting autophagy via ATG7 suppression [ 186 ]. In NSCLC, miR-143 inhibits cancer cell growth by downregulating ATG2B at both the mRNA and protein levels [ 187 ]. Overexpression of tumor-suppressive microRNAs that are typically underexpressed in various cancers can impede tumor progression by inhibiting neoplastic cell growth [ 188 ]. In human glioblastoma, overexpression of miR-224-3p inhibits the precursor stages of autophagy under hypoxic conditions by targeting ATG5 and FIP200 [ 189 ]. YY1 has been identified as a promoter of SQSTM1 expression, activating autophagy by epigenetically repressing miR-372; elevated miR-372 levels, however, diminish the cytoprotective effects of autophagy in breast cancer, as demonstrated in vivo [ 190 ].

The intricate relationship between onco-miRNAs and autophagy-related genes exhibits distinct oncogenic characteristics. For instance, in NSCLC, the overexpression of miR-18a-5p has been shown to drive tumorigenesis by targeting interferon regulatory factor 2 (IRF2), thereby inhibiting cellular proliferation through mechanisms involving apoptosis and protective autophagy [ 191 ]. The microRNA known as miR-30e, which plays a critical role in inhibiting the autophagic process by specifically targeting the 3’ untranslated region (3’UTR) of the autophagy-related gene ATG5 , is notably suppressed by the compound 3,3’-diindolylmethane (DIM), an indole derivative demonstrated to possess antitumor properties, leading to a consequential reduction in the proliferation of gastric cancer cells [ 192 ].

Histone modification

The intricate process of chromatin remodeling encompasses a multitude of histone covalent modifications, including acetylation, phosphorylation, and methylation [ 193 ]. The transcriptional state of chromatin can be modulated by numerous associated protein complexes that either enhance promoter activity or refine gene expression. Several of these complexes respond to DNA modifications and to histone alterations that arise under different contextual conditions. Specific histone residues are critically important for maintaining genome integrity, regulating gene expression, and preventing cancer, particularly given the delicate balance required in histone methylation [ 194 – 196 ]. The N-terminal amino acid tails of core histones, particularly those of histones H3 and H4, are characterized by their protruding structure and charged nature, rendering them prime targets for a wide array of intricate post-translational modifications, which notably include methylation [ 197 ], acetylation [ 198 ], phosphorylation [ 199 ], ubiquitination [ 200 ], sumoylation [ 201 ] and ADP ribosylation [ 202 , 203 ].

Histone modification patterns, much like DNA methylation signatures, have been utilized as biomarkers to aid in the diagnosis of multiple cancers. Reduced levels of H3K9ac, H3K9me3, and H4K16ac have been associated with an increased risk of non-small cell lung cancer, suggesting their potential prognostic relevance [ 204 ]. Notably, loss of H3K9me3 has been observed in AML, particularly within the core promoter regions of various genes, suggesting a potential mechanism contributing to leukemogenesis [ 205 ].

Across these malignancies, a spectrum of genetic alterations, including deletions, somatic mutations, and amplifications, dysregulate HMTs and HDMs, ultimately altering their enzymatic functions [ 206 ]. Elevated EZH2 expression has also been linked to greater tumor aggressiveness and poorer prognosis in breast cancer [ 207 ]. In lung cancer, silencing of the EP-CAM gene is mediated by the H3K9 methyltransferase G9a, which promotes both invasion and metastasis, further illustrating the critical role of histone-modifying enzymes in cancer progression [ 208 ].

Histone methylation at H3K9 is further regulated by hypoxic conditions in tumors, which enhance the stability of the G9a protein and thereby influence chromatin-remodeling factors. Downregulation of gene expression through DNA methylation plays a central role in promoting tumor progression. At the same time, certain genes become activated through enzymatic modifications that reshape the epigenomic landscape, a paradoxical process that drives tumor development by silencing essential genes and disrupting the homeostatic balance required for maintaining cellular integrity [ 143 ]. To maintain methylation equilibrium, a diverse set of histone demethylases has evolved to remove methyl groups from specific residues, thereby counteracting the actions of methyltransferases across various histone marks. Two major histone demethylase families have been identified, each mediating these processes through well-characterized biochemical mechanisms. Lysine-specific demethylase 1 (LSD1) was the first demethylase identified for its ability to target H3K4me1 and H3K4me2. Subsequent studies demonstrated that LSD1 can also demethylate H3K9me1 and H3K9me2, further elucidating the complex regulatory mechanisms governing histone methylation and demethylation in cancer biology [ 209 , 210 ].

In the demethylation of multiple substrates, LSD1 is well known to employ a flavin adenine dinucleotide (FAD)-dependent amine oxidation reaction as its primary catalytic mechanism [ 211 ]. This reaction endows LSD1 with considerable functional versatility, enabling it to interact with diverse protein partners and participate in numerous biological processes essential for cellular homeostasis [ 212 ]. The reliance on FAD also suggests a mechanistic link between cellular metabolic status and gene expression regulation, a relationship critical for maintaining epigenomic stability and preventing metabolic perturbations from disrupting chromatin states [ 213 ].

In addition, several proteins containing a catalytic Jumonji C (JMJC) domain constitute a second class of histone demethylases, highlighting the diversity of enzymatic mechanisms that regulate histone methylation [ 214 ]. These enzymes mediate demethylation via a dioxygenase reaction that requires Fe (II) and the cofactor alpha-ketoglutarate, underscoring the importance of metabolic intermediates in shaping epigenetic outcomes. The central role of alpha-ketoglutarate further emphasizes how cellular metabolic pathways and environmental cues converge to influence patterns of gene activation and silencing [ 215 ]. In contrast to LSD1, JMJC domain–containing demethylases, such as JHDM3A, can remove trimethyl groups from histone residues, including H3K9me3 and H3K27me3, thereby demonstrating distinct and expanded catalytic capabilities [ 216 , 217 ].

More recently, it has become evident that the enzymatic activity of HDMs is profoundly affected by deregulation and mutations across multiple biological contexts. Furthermore, several HDMs have been examined using knockout mouse models that exhibit severe phenotypes, including lethality, underscoring the essential role of proper HDM expression levels in supporting normal development and overall organismal viability [ 143 ].

In oncology, it is well established that histone acetylation and deacetylation are recurrent and significant mechanisms that modulate autophagy, an essential cellular degradation pathway [ 218 ]. Furthermore, HDAC7 has been identified as an oncogenic factor in salivary mucoepidermoid carcinoma, making it a compelling therapeutic target. Evidence indicates that HDAC7 inhibition suppresses cell growth, largely by downregulating the cMyc oncogene. In addition to reducing proliferative capacity, HDAC7 inhibition induces cell cycle arrest and promotes both autophagy and apoptosis, underscoring its multifaceted contribution to cancer biology [ 219 ]. Similarly, HDAC10 has been implicated in activating pro-survival autophagy mechanisms that support cancer cell growth and confer resistance to cytotoxic agents in neuroblastoma, suggesting that this HDAC isoform may represent a viable druggable target in high-grade cancers [ 220 ]. Additionally, acetylated FoxO1 has been shown to activate autophagy by interacting with Atg7 , thereby inducing apoptosis in human colon cancer and mouse xenograft models [ 221 ].

Under typical conditions, PCAF (P300/CBP-associated factor) is predominantly observed in a repressed state in HCC. However, when PCAF is upregulated in HCC, it is associated with autophagy activation, thereby facilitating mechanisms that inhibit cancer both in vitro and in vivo [ 222 ]. The condition known as prostatic intraepithelial neoplasia (PIN) arises from diminished autophagic activity, which is directly linked to the homozygous deletion of the SIRT1 gene, a critical regulator of cellular function. The expression patterns associated with the suppression of androgen-responsive genes, alongside the activation of autophagy by endogenous SIRT1 in the prostate, provide compelling evidence for its role as a tumor suppressor and a regulatory checkpoint in the pathogenesis of PIN [ 223 ]. Modulation of autophagy through histone acetylation can, in some cases, inadvertently promote tumorigenesis. HDAC8, for example, is overexpressed in oral squamous cell carcinoma (OSCC), yet its inhibition suppresses cancer cell proliferation by activating apoptotic pathways, suggesting that combining autophagy inhibitors with HDAC8 inhibitors may represent a promising therapeutic strategy for OSCC [ 224 ]. Epithelial-to-mesenchymal transition has also been closely linked to p62-mediated repression of autophagy, which sustains elevated HDAC6 levels in aggressive prostate cancer, underscoring the complexity of these interconnected processes. Cancer cell growth is further promoted by impaired autophagosome maturation driven by p300-mediated acetylation of Atg6 at lysines 430 and 437, establishing a connection between acetylation events and enhanced tumor proliferation [ 225 , 226 ].

Histone modifications can play a pivotal role in activating organelle-specific autophagy in cancer. For instance, SIRT3 has been shown to confer protection against apoptotic cell death in glioma cells by promoting mitophagy, a process involving the interaction between VDAC1 and parkin [ 227 ]. The intricate relationship between autophagy-related mechanisms and cancer modulation has been documented to exhibit significant correlations with histone methylation and demethylation [ 228 ]. The formation of autophagosomes, critical components of the autophagy pathway, is effectively impeded by histone methyltransferase G9a, a molecule highly expressed in a diverse array of cancers, through transcriptional repression of the genes LC3 and WIPI1 [ 229 ]. The downregulation of lysine-specific demethylase 2B, a member of the JHDM family commonly associated with gastric cancer that functions as a histone lysine demethylase, has been shown to inhibit the proliferation of cancer cells in in vitro studies, as well as in gastric cancer xenograft models, primarily by facilitating the activation of autophagy [ 230 ]. Conversely, inhibition of lysine-specific demethylase 4 A can reduce glioma cell survival by activating autophagy, suggesting its potential as a promising biomarker for the treatment of aggressive gliomas [ 231 ]. The proliferation of neuroblastoma cells can be effectively suppressed by inhibiting G9a, an H3K9 methyltransferase, which triggers autophagy by up-regulating autophagy-associated genes and increasing LC3B expression [ 232 ]. The activation of Beclin-1 , a critical regulator of autophagy, induces autophagy by inhibiting euchromatic histone-lysine N-methyltransferase 2, thereby impeding breast cancer cell growth [ 233 ].

ATP-dependent chromatin remodeling

Inhibitors of histone modifiers are currently under investigation in numerous clinical trials as emerging epigenetic therapeutic strategies for cancer [ 234 ]. Although the interplay between the SWI/SNF complex, which mediates nucleosome remodeling, and the broad spectrum of proteins that modify histone covalent structures is well documented, the precise molecular interactions between these two protein classes remain insufficiently understood [ 235 ]. Moreover, it is not yet clear how dysfunction of the SWI/SNF complex influences the activity of other chromatin-modifying proteins or alters their responsiveness to epigenetic therapies targeting these modifiers. This gap presents a compelling avenue for future research, with the potential to clarify interpatient variability in therapeutic response [ 236 , 237 ]. The two ATPase subunits of the SWI/SNF complex, BRM and BRG1, have emerged as promising targets for novel cancer therapies. In a study involving ten different cancer cell lines in which SMARCA2 , the gene encoding BRM, was silenced, butyrate (a broad-spectrum HDAC inhibitor) was found to upregulate or even restore SMARCA2 expression. However, once butyrate treatment was discontinued, SMARCA2 expression returned to its silenced state, suggesting the involvement of a reversible regulatory mechanism. Notably, despite the restoration of SMARCA2 expression, BRM did not regain functional activity in a biological context, an outcome likely attributable to concomitant histone deacetylation, which BRM in its altered state is unable to recognize effectively [ 238 ]. This observation carries significant ramifications for the clinical application of HDAC inhibitors, underscoring the critical need to develop a more selective HDAC inhibitor that effectively restores Brahma (BRM) function. In cancer cell lines deficient in the BRG1 gene, subsequent depletion of BRM is likely to precipitate cellular senescence, as evidenced by previous research [ 239 ]. Consequently, it is plausible to deduce that, despite the established understanding of their distinct yet complementary roles, BRM may be compensating for the absence of BRG1 by contributing to the formation of residual SWI/SNF complexes, as supported by multiple studies [ 240 , 241 ]. The identification of a synthetic lethal interaction underscores the potential of BRM as a viable therapeutic target, specifically in cells lacking BRG1 , and this finding further implies that chromatin remodelers, in general, are promising candidates for future drug design initiatives [ 239 ]. Table 3 provides a mechanistic overview of the principal epigenetic regulatory processes involved in cancer.

Metabolic and molecular links between nutrition and epigenetic regulation in cancer

One-carbon metabolism and methyl-donor availability

One-carbon metabolism constitutes a major biochemical interface between nutrient availability and epigenetic regulation. This interconnected network integrates folate- and methionine-dependent pathways to generate one-carbon units required for nucleotide synthesis, redox homeostasis, and methyl-group transfer. Within this system, folate, choline, betaine, vitamin B12, vitamin B6, and methionine serve as key nutritional inputs that regulate the synthesis and recycling of S-adenosylmethionine (SAM), the principal methyl donor for DNA and histone methylation reactions. In parallel, the accumulation of S-adenosylhomocysteine (SAH), a product of methyl-transfer reactions, is also critical because the SAM/SAH ratio is a major determinant of cellular methylation capacity. Accordingly, variation in dietary methyl-donor availability can influence both global and locus-specific methylation patterns, with potential consequences for oncogene activation, tumor suppressor gene silencing, and chromatin organization in cancer [ 242 – 245 ].

Folate provides one-carbon units for tetrahydrofolate-dependent reactions, whereas vitamin B12 acts as an essential cofactor for methionine synthase, which remethylates homocysteine to methionine. Choline and betaine offer an additional methyl-donor pathway through betaine-homocysteine methyltransferase, thereby supporting methionine regeneration and downstream SAM synthesis. Because SAH is a potent feedback inhibitor of methyltransferases, disruption of methyl-donor intake or one-carbon flux can affect not only SAM abundance but also the efficiency of methylation reactions. This is particularly relevant in cancer, where both DNA methyltransferases and histone methyltransferases depend on SAM as a substrate, linking nutrient-dependent metabolic changes directly to epigenetic remodeling [ 243 , 244 , 246 ].

Beyond its effects on overall methyl-donor status, one-carbon metabolism can also influence promoter-specific and context-dependent epigenetic regulation. Experimental evidence suggests that histone methylation may be especially sensitive to fluctuations in methionine metabolism and SAM availability, indicating that nutrient status may affect selective chromatin marks rather than only broad genome-wide methylation. At the same time, cancer cells frequently reprogram one-carbon metabolism to support proliferation and survival, coupling metabolic adaptation to epigenetic plasticity. Thus, nutrient sufficiency or imbalance not only supports cellular biomass but may also reshape the epigenetic architecture that governs transcriptional programs, differentiation states, and therapeutic responsiveness in malignant cells [ 243 , 244 , 247 ].

Microbiome-derived short-chain fatty acids as endogenous epigenetic regulators

A second major link between diet and the cancer epigenome is mediated by the gut microbiome. Fermentation of non-digestible dietary fiber by intestinal microbes generates short-chain fatty acids (SCFAs), primarily acetate, propionate, and butyrate. Among these, butyrate and propionate are particularly relevant to epigenetic regulation because they possess histone deacetylase (HDAC)-inhibitory activity. Through HDAC inhibition, these metabolites increase histone acetylation, alter chromatin accessibility, and modulate gene expression in ways that influence cell-cycle regulation, differentiation, apoptosis, immune function, and tumor behavior. Thus, microbial metabolism of dietary fiber translates a dietary exposure into a direct chromatin-modifying signal [ 248 – 250 ].

Butyrate is the most extensively characterized SCFA in this context and is widely recognized as an endogenous HDAC inhibitor. In cancer models, particularly colorectal systems, butyrate has been shown to promote histone hyperacetylation and regulate transcriptional programs associated with growth arrest, differentiation, and apoptosis. Propionate is generally considered a less potent HDAC inhibitor than butyrate, but it also exhibits epigenetic activity and can influence histone acetylation and inflammatory signaling under specific conditions. These effects extend beyond tumor-cell intrinsic pathways, as SCFAs also modulate immune-cell activity, cytokine responses, and the tumor microenvironment. Accordingly, microbiome-derived SCFAs are increasingly recognized as endogenous epigenetic mediators linking dietary fiber intake to cancer-associated transcriptional regulation [ 251 – 254 ].

The biological significance of this pathway is shaped by metabolic context. In normal colonocytes, butyrate is efficiently oxidized as an energy substrate, whereas in colorectal cancer cells, altered metabolism may favor butyrate accumulation and thereby enhance its HDAC-inhibitory and transcriptional effects. This context-dependent activity may partly explain the repeatedly observed association between dietary fiber, microbial metabolism, and antitumor phenotypes, particularly in the colorectum. More broadly, the epigenetic actions of butyrate and propionate further support the concept that diet influences chromatin not only through exogenous bioactive compounds, but also through host-microbe co-metabolism and the generation of endogenous epigenetically active metabolites [ 248 , 255 – 257 ].

Genetic variation and inter-individual epigenetic responsiveness

Inter-individual variability in epigenetic responsiveness represents an important component of precision nutrition in cancer. Nutrient-dependent epigenetic regulation is influenced not only by dietary exposure, but also by inherited variation in genes involved in one-carbon metabolism, methyl-group transfer, and related metabolic pathways. In this context, single-nucleotide polymorphisms (SNPs) in enzymes such as methylenetetrahydrofolate reductase (MTHFR) are particularly relevant because they can modify folate utilization, homocysteine remethylation, and methyl-donor availability, thereby affecting the SAM/SAH balance and downstream DNA and histone methylation capacity. The common MTHFR C677T variant, for example, is associated with reduced enzymatic activity and has been linked to altered methylation biology, especially under conditions of low folate availability. These observations support the concept that diet-related epigenetic effects may differ substantially between individuals according to inherited variation in nutrient metabolism [ 246 , 258 , 259 ].

Evidence from cancer-related studies further suggests that genetic variation in one-carbon metabolism may contribute to epigenetic heterogeneity across tumor types [ 259 ]. Reviews of breast cancer have emphasized that the biological consequences of folate-related exposures may be modified by MTHFR polymorphisms, with some data indicating that reduced MTHFR activity in the setting of low folate intake may be associated with increased breast cancer risk [ 260 ]. In colorectal cancer, germline variation in one-carbon metabolism genes has also been associated with differences in tumor methylation markers, including global methylation measures such as LINE-1, supporting a link between host genotype and somatic epigenetic architecture[ 260 , 261 ]. These findings indicate that inherited variation in nutrient-sensitive metabolic pathways may shape the magnitude and direction of diet-related epigenetic responses, thereby providing a mechanistic basis for precision nutrition approaches in cancer prevention and management.

The effects of nutrition on epigenetic regulation

Extensive epidemiological and clinical evidence indicates that dietary factors play a significant role in cancer development, reflecting a complex interaction between nutrition and oncogenesis. Dietary mutagens, which can induce genetic mutations, disrupt normal cellular pathways, and contribute to various biological and pathological processes that precipitate cancer [ 262 ]. Conversely, numerous studies have demonstrated that specific dietary patterns and components exert protective effects, in part because DNA metabolism and repair depend on essential dietary cofactors required across multiple metabolic pathways [ 263 ]. Bioactive food compounds can contribute to cancer prevention through epigenetic mechanisms, nutrient–gene interactions, and the attenuation of oxidative stress, as documented in the literature [ 264 ].

Individual food preferences and the quantity of specific dietary components consumed markedly influence gene expression and overall genomic integrity. Phytochemicals and polyunsaturated fatty acids have been extensively investigated for their contributions to the diet–cancer relationship [ 265 ]. Vitamins and minerals also play critical roles in this multifaceted interaction. Compounds such as polyphenols, phenolic acids, carotenoids, flavones, flavanols, soy-derived isoflavones, and sulfur-containing metabolites remain subjects of active scientific investigation [ 266 ]. Examples include lycopene from tomatoes, resveratrol from grapes and berries, curcumin from turmeric, hesperidin from citrus fruit, carotenoids in red produce, ascorbic acid, chlorogenic acid from coffee, soluble fibers, and polyunsaturated fatty acids from marine sources, all of which have been associated with protective effects against cancer [ 33 ].

Dietary vitamins and minerals are essential for numerous regulatory and enzymatic processes in human physiology, and deficiencies in these micronutrients can produce significant health consequences. Zinc and folate, in particular, are crucial for DNA repair, although their mechanistic roles may vary. Some dietary compounds influence epigenetic regulation, while others interact with genetic material through pathways beyond DNA repair and methylation. Many also protect against oxidative damage or inhibit cellular proliferation by modulating inflammatory signaling [ 267 ].

For example, adequate folate intake has been associated with a decreased risk of colorectal cancer, though individual susceptibility varies due to genetic heterogeneity [ 268 ]. Similarly, the risk associated with red meat consumption and colorectal cancer varies across individuals owing to genetic variations that affect metabolic pathways [ 269 ]. Higher intake of cruciferous vegetables has been associated with reduced lung and colorectal cancer risk, and these vegetables contain a bioactive compound known to confer health benefits [ 270 ]. Figure 3 illustrates how nutritional factors influence key components of epigenetic regulation.

Caloric restriction, ketogenic diets, and epigenetic regulation in cancer

Caloric restriction (CR), defined as a substantial reduction in caloric intake (30%–40%) while maintaining adequate nutritional support, and the pharmacological agent rapamycin are widely recognized for their potential to extend lifespan across multiple organisms. Although the precise biochemical and molecular mechanisms underlying their longevity-promoting effects remain incompletely understood, the epigenome, encompassing the full spectrum of chemical modifications to DNA and histone proteins that regulate gene expression without altering the genetic sequence, is considered a principal target. Other critical factors implicated in these effects include genomic stability, protein quality control, telomere dynamics, mitochondrial function, nutrient-sensing pathways, cellular senescence, stem cell exhaustion, stress-response mechanisms, and intercellular communication, as supported by numerous studies [ 271 – 273 ].

The pioneering research conducted by McCay et al. was instrumental in the scientific literature, as they were the first to provide empirical evidence that adherence to a CR diet resulted in a notable extension of the lifespan of laboratory mice [ 274 ]. Following this seminal finding, a plethora of additional studies have consistently demonstrated a positive correlation between CR and increased lifespan across a diverse array of organisms, which encompasses unicellular eukaryotes such as yeast, multicellular organisms including nematodes and fruit flies, aquatic species like fish, and even non-human primates (reviewed in [ 275 ]). Among the numerous investigations in this domain, two studies warrant particular attention for their seemingly contradictory findings on the relationship between CR and longevity. Specifically, the research conducted by Colman et al. provided compelling evidence that CR led to a significant extension of lifespan and a concomitant reduction in overall mortality rates among Rhesus monkeys compared with control groups maintained on an ad libitum diet [ 276 , 277 ]. Conversely, the study by Mattison et al. reported that Rhesus monkeys subjected to a CR regimen did not exhibit any measurable extension of lifespan; however, these subjects did demonstrate a decrease in the incidence of certain age-related diseases, including, but not limited to, cancer [ 278 ]. The divergent outcomes observed in these two pivotal studies may be attributable to variations in the composition of the diets administered, which could have differential impacts on the epigenetic profiles of the subjects involved, and it is also plausible that the inherent epigenetic characteristics of the animals themselves could differ between the two experimental setups, particularly given that they were not conducted under identical environmental conditions. It has been well established that both environmental factors and lifestyle choices profoundly shape organisms’ epigenetic landscapes [ 279 ].

Numerous intricate mechanisms underlying CR’s effects on lifespan extension can be meticulously examined and considered. One of the most immediate and direct outcomes stemming from the implementation of CR is the consequent reduction in the energy status within the organism, which is intricately linked to a concomitant decline in various metabolic parameters, including but not limited to blood glucose levels, insulin concentrations, insulin-like growth factor 1 (IGF-1), levels of growth hormones, and a multitude of other relevant hormones as comprehensively reviewed in the literature [ 280 ]. The observed diminishment in the energy status of cellular systems inevitably leads to a reduction in mitochondrial activity, which in turn results in a decrease in aerobic respiration; this biochemical alteration subsequently elevates the ratio of adenosine monophosphate to adenosine triphosphate (AMP/ATP) while also increasing the concentrations of nicotinamide adenine dinucleotide (NAD+). Furthermore, two pivotal cellular sensors that monitor nutrient availability and energy levels, specifically adenosine monophosphate-activated protein kinase (AMPK) and sirtuin 1 deacetylase (SIRT1), are activated in response to these changes [ 281 – 283 ]. The activation of AMPK triggers a cascade of physiological events that culminate in a notable reduction in fatty acid synthesis, oxidation, and cholesterol biosynthesis; conversely, the active form of SIRT1 may enhance processes such as ketogenesis and lipolysis while simultaneously reducing glycolytic activity. It is important to note that additional proteins may also play significant roles in mediating these complex biochemical processes [ 284 ].

The ramifications of CR on the epigenome were initially posited to be associated with increased genomic stability, primarily through the mitigation of DNA methylation loss over time [ 285 ]. However, subsequent research conducted by Issa’s laboratory revealed that epigenetic drift, characterized by both gains and losses of DNA methylation across various genomic loci, was not only conserved across multiple species but also correlated with lifespan and CR [ 286 ]. More recently, a study by Hernando-Herraez demonstrated that mouse stem cells accumulate epigenetic drift through the accrual of stochastic changes in DNA methylation patterns at the promoters of numerous genes; this accumulation ultimately leads to alterations in transcriptional regulation and contributes to stem cell aging [ 287 ]. In light of these findings, various epigenetic mechanisms have been proposed to underlie the anti-aging effects of CR, and these hypotheses have been supported by multiple empirical studies and reviews in the field [ 279 , 280 , 283 , 284 , 288 – 290 ].

Certain malignancies, notably those affecting the brain, as well as cancers of the head and neck region, in addition to lung cancers, are characterized by a significant reliance on glucose for their metabolic processes, thereby suggesting that patients diagnosed with these specific types of tumors might derive potential therapeutic advantages from adhering to a dietary regimen that restricts glucose intake, such as the ketogenic diet, which is low in carbohydrates [ 291 , 292 ]. However, it is imperative to note that, in the broader context of cancer research and treatment, CR has not been conclusively shown to exert direct anticancer effects across the spectrum of malignancies, as highlighted in the literature [ 292 ]. The implementation of a CR diet, alongside the ketogenic dietary framework, has been associated with increased fatty acid oxidation and the production of acetyl-CoA, a pivotal metabolite in cellular energy metabolism. This biochemical transformation subsequently leads to increased β-hydroxybutyrate synthesis, a compound that serves as an alternative energy source for the brain while also inhibiting glycolytic processes, further complicating the relationship between diet and cancer cell metabolism [ 293 ]. Consequently, although a CR diet may enhance the antioxidant defense mechanisms of normal, healthy tissues, this beneficial effect does not extend to cancer cells, which frequently exhibit distinct metabolic adaptations [ 294 ].

In malnourished cancer patients, the rationale for recommending a CR diet is tenuous. It has even been proposed that a diet high in fats and proteins may more effectively meet the specific nutritional requirements of individuals with cancer than restrictive diets that impose caloric limitations [ 295 ]. It is crucial to recognize that findings derived from research conducted on obese individuals or experimental animal models cannot be directly extrapolated to human cancer patients, particularly those who are advanced in age and may present with different metabolic and nutritional needs [ 296 , 297 ]. Conversely, it is a well-documented reality that elderly cancer patients frequently suffer from malnutrition, thereby rendering it a precarious choice for healthcare professionals to advocate for any type of restrictive dietary intervention [ 298 ]. At present, it is advisable to consider only tumors that demonstrate a pronounced dependence on glucose metabolism for dietary modifications of this nature, while ensuring that each case is approached with careful consideration of the unique circumstances surrounding the patient, particularly those factors associated with the aging process [ 299 ]. Recent studies have indicated that incorporating specific foods into the diet, such as grapes, known for their resveratrol content; soy products, which contain genistein; an array of cruciferous vegetables; and green tea, may confer protective effects against the dual challenges of aging and cancer development [ 33 ]. Furthermore, numerous studies have demonstrated that dietary patterns that include these beneficial substances, often referred to as an “epigenetic diet,” are associated with a decreased incidence of certain diseases, drawing parallels to the effects observed with CR diets [ 300 , 301 ].

Nutritional compounds

Nutritional epigenetics and phytochemicals

Phytochemicals, abundant in many fruits and vegetables and recognized for their antioxidative properties, function as epigenetic modulators that play key roles in the pathophysiological mechanisms underlying cancer. These compounds have been shown to inhibit DNMTs, modify histones, and alter microRNA levels, thereby influencing the expression of multiple tumor suppressor genes in neoplastic conditions [ 302 ]. Phytochemicals can either activate or repress specific microRNAs to counteract oncogenic microRNAs or modulate the levels of tumor-suppressive microRNAs. Empirical evidence indicates that phytochemicals modify the expression profiles of microRNAs and their target mRNAs, thereby affecting diverse biological processes, including apoptosis, cellular proliferation and differentiation, angiogenesis, and metastasis in cancer [ 303 ].

The qualitative aspects of dietary intake are equally significant as its quantitative aspects in extending lifespan and preventing the onset of various health conditions. Nutritional constituents that aim to target, manage, and avert specific diseases have emerged as a critical domain, given that dietary patterns can affect epigenetic modifications. The expression “epigenetic diet” refers to a nutritional regimen centered on the intake of specific foods, such as soy, grapes, cruciferous vegetables, and green tea, which activate epigenetic processes that confer protection against oncogenesis and senescence [ 33 , 275 ]. Key components of the epigenetic diet include epigallocatechin-3-gallate (EGCG, found in green tea), genistein (from soy), resveratrol (derived from grapes), apigenin (found in parsley and celery), as well as other nutritional elements and specific dietary components. The incorporation of these food categories into a conventional dietary framework may be regarded as a viable therapeutic approach for treating diseases, due to their potential to reduce the prevalence of various ailments, particularly malignancies [ 301 ].

Dietary polyphenols and changing the epigenome of cancer cells

Polyphenols, also referred to as polyhydroxy phenols, are present in various fruits and vegetables and constitute an integral component of the human diet, commonly termed dietary polyphenols [ 304 ]. These compounds are categorized as secondary metabolites synthesized by plants via the Shikimate pathway [ 305 ]. Based on their distinct chemical characteristics and structural configurations, polyphenols can be broadly classified into several major categories and subclasses, including phenolic acids, flavonoids, stilbenes, lignans, and other related polyphenolic compounds [ 305 , 306 ]. All polyphenols are characterized by the presence of at least one aromatic ring and a minimum of one hydroxyl group. They are derived from phenylalanine or its precursor, shikimic acid, and exhibit a wide range of chemical properties and structures, from simple to complex. They often incorporate one or more sugar moieties attached to one or more hydroxyl groups [ 307 ]. Over 800 distinct polyphenols have been identified. Epigallocatechin is a prevalent polyphenol found in the human diet, sourced from green tea, while turmeric acid is derived from cinnamon, resveratrol is obtained from grapes, and curcumin is extracted from turmeric. Numerous studies have substantiated that dietary polyphenols confer significant health benefits, including the potential for cancer prevention [ 304 , 308 ]. Various mechanisms have been elucidated by which dietary polyphenols mitigate certain diseases, including their epigenetic roles in cancer prevention through remodeling of chromatin structure and activation of gene silencing pathways. The cancer-preventive effects of dietary polyphenols can be attributed to their capacity to inhibit DNA methyltransferase activity and to modify histone proteins. These attributes of polyphenols possess the potential to fundamentally alter the epigenome of tumor cells, thereby representing intriguing prospects for cancer prevention [ 309 , 310 ]. However, interpretation of these findings requires caution, because several reported epigenetic effects of dietary polyphenols derive from preclinical models or from in vitro concentrations that may exceed physiologically achievable exposure in humans. Figure 4 depicts the epigenetic effects of dietary polyphenols on cancer cells.

Food sources and epigenetic functions

Omega-3 fatty acids

Omega-3 fatty acids, classified as polyunsaturated fatty acids, contain a double bond at the third carbon atom according to the omega naming system, which is used to characterize their chemical structure. These essential fatty acids are found predominantly in fatty and oily fish such as salmon and mackerel, and in smaller amounts in plant-derived oils, including flaxseed oil. Their efficacy as potent anti-inflammatory agents is well documented, with numerous studies demonstrating protective effects against a wide range of diseases, most notably cardiovascular disorders and various cancers. There is also compelling evidence supporting their nutrigenetic functions, as omega-3 fatty acids interact with specific genes involved in inflammation and cancer development, thereby influencing gene expression and associated health outcomes [ 311 ]. Numerous in vitro studies conducted on animal models have elucidated the protective effects of omega-3 fatty acids, particularly docosahexaenoic acid (DHA), against the progression of prostate cancer, demonstrating a significant correlation between these fatty acids and tumor suppression [ 312 ]. The two primary omega-3 fatty acids, DHA and eicosapentaenoic acid (EPA), are obtained predominantly from oily fish, and extensive epidemiological evidence indicates that regular consumption of such fish is inversely associated with prostate cancer risk. Polyunsaturated fats, including both n-3 and n-6 fatty acids, are metabolically converted into eicosanoids, biologically active compounds such as prostaglandins and thromboxanes. These eicosanoids play essential roles in numerous physiological processes, including cell growth and differentiation, immune modulation, and regulation of anti-inflammatory responses [ 313 ]. The mechanism by which omega-3 fatty acids inhibit carcinogenesis primarily involves their ability to suppress the synthesis of eicosanoids derived from arachidonic acid, a fatty acid that serves as a precursor to pro-inflammatory compounds [ 314 ]. Eicosanoids, which are typically synthesized endogenously from fatty acids, can vary significantly in their effects; those derived from arachidonic acid are known to elicit pro-inflammatory responses, while those derived from omega-3 fatty acids are associated with anti-inflammatory effects, thereby providing protection against prostate cancer. In the intricate process of eicosanoid synthesis, the enzyme cyclooxygenase-2 ( COX-2 ) is recognized as a pivotal catalyst, and research has indicated that there is an overproduction of COX-2 in individuals diagnosed with prostate cancer, which contributes to the malignancy’s progression [ 315 , 316 ]. Moreover, the consumption of non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit COX-2 production, has been linked to a reduced risk of developing prostate cancer, further emphasizing the importance of this enzyme in cancer pathology [ 314 , 316 ]. A comprehensive case–control study conducted in Sweden reported a statistically significant association between salmon consumption (rich in n-3 fatty acids) and a COX-2 genetic variant that modulates prostate cancer risk [ 317 ]. Among individuals who were heterozygous or homozygous for the variant allele of the þ6365T/C single-nucleotide polymorphism (SNP) in COX-2 , high salmon intake was associated with a marked reduction in prostate cancer risk, whereas no significant association between fish consumption and tumor risk was observed in carriers of the wild-type allele [ 318 ]. Marine-derived n-3 unsaturated fatty acids have also been shown to protect against breast carcinoma in postmenopausal women, underscoring the broader implications of omega-3 fatty acids in cancer prevention. This inhibitory effect on breast cancer is closely linked to lipid peroxidation levels in tumor tissues or cells, reinforcing the role of omega-3 fatty acids in mitigating oxidative stress and its associated carcinogenic processes [ 317 , 319 ].

Epigallocatechin

Polyphenolic compounds derived from traditional tea, particularly green tea, have been extensively documented for their significant contributions to the prevention and management of various diseases, including cancer, which remains one of the most pressing health challenges globally [ 320 ]. Within the broader classification of tea polyphenols, a specific subgroup known as catechins has garnered considerable attention; this subgroup encompasses compounds such as EGCG, epicatechin (EC), and epigallocatechin (EGC), each of which shares similar biochemical properties and has been substantiated in numerous studies for its potential protective roles against the onset of cancer [ 321 ]. Among these catechins, epigallocatechin stands out, accounting for approximately 50% of the bioactive constituents in tea that have been rigorously studied for their anticarcinogenic effects and mechanisms of action. A plethora of research studies have demonstrated a statistically significant positive correlation between the intake of epigallocatechin and the subsequent prevention of various types of cancer, including but not limited to oral, breast, skin, esophageal, colorectal, prostate, head and neck, and pancreatic cancers [ 322 ]. The cancer-preventive effects of epigallocatechin and epicatechin gallate are closely linked to DNA methylation, a key epigenetic modification that regulates gene expression. The enzyme catechol-O-methyltransferase (COMT) inactivates catechol molecules by methylating epigallocatechin. In this biochemical process, SAM serves as the methyl donor, and the COMT-mediated transfer of a methyl group to catecholamines converts SAM into SAH. SAH is a potent inhibitor of DNMTS, thereby altering DNA methylation status [ 323 , 324 ]. The epigenetic influences of epigallocatechin gallate, in particular, manifest through various mechanisms, including modifications to epigenetic landscapes, induction of cell cycle arrest, promotion of programmed cell death (apoptosis), mitigation of oxidative stress, and inhibition of angiogenesis, all of which are critical processes in cancer development. Furthermore, epigallocatechin gallate has been shown to inhibit tumor cell proliferation and modulate specific signal transduction pathways, thereby influencing cellular behavior [ 307 ]. Given that methylation often silences genes, epigallocatechin gallate has been shown to reactivate silenced genes by directly interacting with DNMT enzymes, thereby facilitating demethylation of these critical regulatory proteins [ 325 – 327 ]. Experimental treatments involving esophageal cancer cells exposed to epigallocatechin gallate have demonstrated a marked reduction in DNMT activity, along with a time- and dose-dependent restoration of methylation in key genes such as hMLH1 , p16 , RARb , and MGMT [ 328 , 329 ]. Additionally, a variety of animal studies have demonstrated that the application of green tea extracts in models of prostate cancer leads to a significant reduction in tumor markers, which include matrix metalloproteinases MMP9 and MMP2, as well as vascular endothelial growth factor A (VEGFA), along with alterations in the phosphoinositide 3-kinase (PI3K) signaling pathway [ 330 ]. In human studies focused on prostate cancer, it has been shown that the introduction of LNCap prostate cancer cells to green tea polyphenols results in the re-expression of GSTP1 genes, thereby highlighting the protective role of GSTP1 against DNA damage induced by reactive oxygen species that are generated as a consequence of hydrogen peroxide (H2O2) exposure [ 330 – 333 ]. A comprehensive investigation of A431 skin malignancy cells has demonstrated that therapeutic exposure to EGCG markedly reduces global DNA methylation, a key epigenetic modification, and significantly decreases levels of 5-methylcytosine [ 334 ]. This effect is accompanied by reduced mRNA expression and enzymatic activity of DNMTs, specifically DNMT1 , DNMT3a , and DNMT3b . Together, these molecular alterations restore expression of the tumor suppressor mRNAs p16 (INK4a) and p21/Cip1 , which play central roles in cell cycle regulation and senescence. Notably, EGCG has also been shown to reactivate estrogen receptor alpha (ERα) expression in breast cancer cells traditionally classified as ERα-negative, such as the MDA-MB-231 cell line, underscoring its potential therapeutic relevance in hormone-resistant breast cancer [ 335 – 337 ]. In a groundbreaking study conducted by Taniguchi’s research group, it was demonstrated for the very first time that there is a significant reduction in the average number of pulmonary nodules, as well as a marked inhibition of lung metastases originating from B16 malignant cells, following the administration of a 0.05% and 0.1% solution of EGCG in C57BL/6 mice, which highlights the anti-metastatic properties of this compound [ 338 ]. DNA microarray analyses comparing wild-type and Nrf2-knockout mice have shown that both Nrf2-independent and Nrf2-dependent genes, particularly those expressed in the liver and small intestine, are significantly modulated by epigallocatechin gallate, demonstrating its broad influence on gene expression pathways [ 339 ]. The administration of EGCG has also been reported to activate key signaling pathways such as Nrf2–antioxidant response element (ARE), Akt, ERK1/2, and heme oxygenase-1 (HO-1) expression in endothelial cells, which are essential for vascular homeostasis, while in B lymphoblasts, it selectively activates the p38 and MAPK pathways involved in cellular stress responses. Another study reported that EGCG induces the expression of Nrf2 -mediated antioxidant genes and activates both the ERK and PI3K pathways in human breast epithelial cells, supporting its multifaceted role in cancer biology and cellular protection [ 340 ].

Apigenin

Apigenin is a flavonoid found in numerous plant-derived foods, particularly in vegetables such as parsley and celery. It has been extensively investigated as a potent anticancer compound that interacts with cancer cells’ genetic material, inhibiting DNA replication and inducing apoptosis across multiple malignancies, including breast, skin, thyroid, prostate, and various leukemias. Apigenin also modulates key cellular mechanisms by inhibiting protein kinase activity, activating caspases, and promoting the generation of reactive oxygen species, collectively contributing to its ability to impede cancer progression and underscoring its potential relevance in cancer prevention [ 341 ]. Furthermore, apigenin has been observed to counteract the diminished viability of dermal fibroblasts that result from exposure to ultraviolet radiation, which is known to cause skin damage, while also exhibiting an anticarcinogenic effect in skin melanoma cells by downregulating the expression of collagenase and matrix metalloproteinase-1 (MMP-1), both of which are involved in the degradation of extracellular matrix components [ 342 ]. In a separate investigation, researchers discovered that apigenin demonstrated substantial anti-proliferative and apoptotic effects by instigating both biochemical alterations and morphological changes in colorectal cancer cell lines such as HT-29 and HCT-15. These compelling findings regarding dietary modifications indicate that apigenin holds significant promise as a powerful dietary phytochemical, with considerable interest in therapeutic interventions, chemopreventive strategies, and the biological processes associated with aging [ 343 ].

Curcumin

Curcumin, a polyphenolic compound found in the widely used spices turmeric and curry, has been shown to play a significant role as a wound-healer, anticancer agent, and anti-inflammatory agent, alongside other health benefits [ 344 ]. Numerous investigations have demonstrated that curcumin inhibits DNMT activity by covalently binding to and blocking the reactive thiolate sites of C1226 on DNMT1 . As a hypomethylating agent, curcumin effectively suppresses the activity of proto-oncogenes and prometastatic genes [ 345 ]. It also exerts epigenomic effects on the genomic DNA of leukemia cells, producing global hypomethylation in MV4-11 cells following curcumin exposure. Extensive genomic analyses have further shown that curcumin prevents colon cancer in a time- and dose-dependent manner by modulating methylation dynamics [ 323 , 327 ]. Curcumin has also been proposed to exhibit anti-inflammatory properties, as described by Valinluck and Sowers. Halogenated cytosine precipitates these effects by activating 5-methylcytosine in DNA methylation [ 33 , 337 ]. Beyond its involvement in DNA methylation, curcumin also functions as a histone-modifying agent with the capacity to inhibit both HDACs and HATs, although this effect is less pronounced than that observed with other dietary polyphenols [ 346 ]. Recent studies have reported a significant reduction in global histone H3 and H4 acetylation in brain tumor cells following curcumin treatment. Additional evidence demonstrates that curcumin induces hypoacetylation at several histone promoter regions, a modification associated with gene silencing [ 347 ]. Curcumin’s ability to inhibit both HDACs and HATs across various disease models, including tumorigenesis, has been supported by recent studies [ 348 , 349 ]. Although the concurrent inhibition of HATs and HDACs may initially appear paradoxical, growing evidence indicates that HAT inhibitors possess meaningful therapeutic potential in cancer and that simultaneous inhibition of HATs and HDACs may represent a promising strategy for tumor management [ 350 ].

Resveratrol

Resveratrol, a specific type of phytochemical extracted from various sources such as red grapes, wine, blueberries, and mulberries, has been extensively studied for its remarkable properties, including potent antioxidant activity, significant anti-inflammatory effects, and impressive anticarcinogenic activity [ 351 , 352 ]. This compound inhibits cancer cell proliferation by downregulating critical growth factors and signaling pathways, specifically IGF, epidermal growth factor (EGF), mitogen-activated protein kinase (MAPK), and the Akt pathway, demonstrating its potential as a therapeutic agent in oncology [ 353 ]. Furthermore, it has been documented in numerous scientific studies that resveratrol serves as an epigenetic regulator, possessing the unique ability to modify DNA methylation patterns and influence the expression of miRNAs, while also demonstrating capabilities to inhibit cellular invasion, diminish angiogenic responses, and suppress the metastasis of tumors specifically in colorectal cancer cells [ 354 ].

Genistein

Genistein, an isoflavone in the flavonoid family and predominantly derived from soybeans, functions as a phytoestrogen with well-recognized anticancer properties. It exhibits dose-dependent epigenetic activity by inhibiting DNMTs, regulating gene expression, and modulating histone acetylation. In esophageal squamous cell carcinoma, genistein reverses DNA hypermethylation and restores the expression of p16 , RARb , and MGMT . Comparable findings have been reported in prostate cancer cells, where genistein reactivates tumor suppressor genes such as p16 and p21 by altering histone marks and promoter methylation [ 330 ]. Similarly, treatment of breast cancer cells with a low concentration of genistein (3.125 µM) results in demethylation of the GSTP1 gene promoter, and genistein has also been shown to reverse BTG3 hypermethylation in renal and prostate cancer cells [ 330 ] [ 314 ]. Research by Fang et al. demonstrated that genistein concentrations ranging from 2 to 20 µM induce methylation changes in transcriptionally silenced genes (including p16INK4a , RARb , and MGMT ) in KUSE 510 esophageal carcinoma cells and in LNCaP and PC3 prostate cancer cell lines [ 355 ]. Similarly, King Batoon et al. reported that re-administration of low-dose genistein (3.125 µM) for one week, with 48-hour intervals, leads to partial demethylation of the tumor suppressor gene GSTP1 in MCF-7, MCF10A, and MDA-MB-468 breast cancer cell lines [ 356 ]. Synergistic use of genistein with DNA methylation inhibitors, including DNMT inhibitors, has further been shown to enhance the reactivation of genes silenced by methylation. Genistein inhibits the activity of DNMT1 , DNMT3a , DNMT3b , and promotes histone acetylation by enhancing HAT activity [ 327 ]. Numerous studies have demonstrated that genistein-induced hypomethylation and hyperacetylation effectively restore tumor suppressor gene expression in prostate cancer cell lines [ 33 , 318 , 323 ].

Sulforaphane

Sulforaphane is a class of phytochemicals prevalent in a variety of vegetables, including but not limited to broccoli, zucchini, and cabbage, and is categorized as an isothiocyanate. This compound exerts modulatory effects on numerous physiological mechanisms through its chemopreventive properties, including cell cycle arrest, apoptosis, and stimulation of xenobiotic metabolic pathways. Moreover, sulforaphane is a robust inhibitor of histone deacetylases (HDACs), promotes histone acetylation, and functions as a regulator of specific genes associated with oncogenesis [ 275 , 302 , 303 , 357 ]. Table 4 highlights nutritional compounds known to exert epigenetic effects and their associated anticancer benefits.

Micronutrients (vitamins and minerals) and changing the epigenome of cancer cells

Minerals and vitamins constitute an integral and indispensable component of the human nutritional framework, encompassing a wide variety of micronutrients that are collectively categorized under the umbrella term Minerals and Vitamins. Both minerals and vitamins play a pivotal role in the intricate biochemical processes that underpin metabolic reactions; they exert regulatory effects on numerous critical physiological events by serving as cofactors and essential nutrients that facilitate these transformations [ 358 ]. A prime illustration of this phenomenon is the methylenetetrahydrofolate gene, which is fundamentally responsible for folate metabolism and the maintenance of normal blood homocysteine levels, a critical aspect of cardiovascular health. Insufficient dietary intake of folic acid is directly correlated with elevated homocysteine levels, a recognized significant biomarker for cardiovascular disease, as illustrated in the literature [ 267 , 359 ]. As previously elaborated, the enzyme DNMT catalyzes the transfer of a methyl group sourced from S-adenosyl methyltransferase to specific sites within the DNA structure and, in return, utilizes its deficient molecules derived from folic acid, vitamin B12, B6, choline, and methionine, thereby underscoring the pivotal role of vitamins within the context of epigenetic mechanisms. Furthermore, substantial protective effects against methylation alterations in lung cancer cells have been documented following multivitamin consumption, suggesting a potential preventive strategy against aberrant methylation patterns [ 360 ].

A deficiency in any dietary methyl donor can significantly alter DNA methylation status, potentially initiating and advancing tumorigenesis. Given that folate serves as a crucial methyl donor, its deficiency has been implicated in the etiology of various cancers, including liver, breast, brain, lung, and colorectal malignancies [ 33 ]. Selenium is an epigenetic mineral abundant in foods such as nuts and beef [ 361 ]. Animal studies provide strong support for selenium’s protective effects against colon and liver cancer, underscoring its relevance in dietary intake. Similarly, zinc is an essential mineral that functions as a cofactor in DNA repair pathways, notably through genes such as OGG1 , which excise oxidized guanine from DNA. Magnesium also plays a crucial role as a cofactor for several DNA polymerases that are indispensable for DNA replication and repair [ 359 ]. Table 5 summarizes key micronutrients and the epigenetic influences they exert in the context of cancer.

Macronutrients and changing the epigenome of cancer cells

Proteins

In tumor biology, cancer cells must undergo metabolic reprogramming that requires adjustments in protein synthesis to sustain relentless proliferation, adapt to the microenvironment, and evade immune detection and destruction. Increased translational activity in certain tumors can be observed microscopically, with an enlarged nucleus, reflecting heightened ribosome production essential for translation, indicating elevated protein biosynthesis and overall cellular metabolism, a phenomenon that may correlate with increased tumor malignancy [ 362 ]. During the complex process of oncogenesis, specific oncogenic signaling pathways, such as c-Myc, RAS, and the PI3K-mTOR pathway, become activated, which, in turn, influence translation and ultimately modulate tumor cell metabolism [ 363 ]. Enzymatic post-translational modifications of proteins encompass a plethora of processes that involve the covalent attachment of a diverse array of molecules to the protein structure, including, but not limited to, phosphorylation, acetylation, glycosylation, and ubiquitination, all of which are critical for the functional regulation of proteins within biological systems. These modifications have been extensively documented in the scientific literature to significantly influence various pathophysiological processes, including oncogenesis and metastasis, and to impact the efficacy of a multitude of anticancer therapeutic regimens [ 364 ]. The transformations that occur at the level of protein metabolism are highly intricate and remain only partially understood, reflecting the complexity of the biochemical interactions that govern cellular function. Given the extensive breadth of this subject, which exceeds the scope of the present review, a detailed discussion of these mechanisms will not be pursued here [ 365 ].

Cancer cells predominantly utilize amino acids not only as essential building materials for their growth and proliferation but also as an energy source that feeds into the Krebs cycle, a central metabolic pathway. Moreover, these amino acids play a critical role in regulating reactive oxygen species (ROS) homeostasis and modulating epigenetic regulation via mechanisms such as DNA methylation and histone acetylation, which are vital for gene expression [ 366 ]. Consequently, substantial scientific effort has been directed toward examining potential correlations between circulating amino acid concentrations and tumorigenesis, the process by which normal cells transform into malignant cells. An analysis of serum levels of 13–21 amino acids in patient blood samples revealed a notable association: high concentrations of histidine, and likely glutamine, were inversely correlated with colorectal cancer risk. These findings suggest that lower levels of these amino acids may confer a protective effect against the development of this malignancy [ 367 ]. Another significant study demonstrated that elevated alanine concentrations in the bloodstream were inversely correlated with colorectal cancer risk. Patients with high alanine levels who were diagnosed with colorectal cancer also exhibited more favorable survival outcomes, leading the authors to propose that alanine may have a protective effect and could serve as a predictive biomarker for improved prognosis [ 368 ]. Conversely, it is noteworthy that elevated levels of aspartate in the bloodstream were positively correlated with an increased risk of developing both prostate and breast cancer, highlighting the complex interplay between amino acid metabolism and cancer pathophysiology [ 369 ].

Methionine, an essential amino acid containing sulfur within its molecular structure, plays a critical role in multiple metabolic processes collectively known as the methionine cycle. Similar to the Warburg effect previously discussed in the context of cancer metabolism, cancer cells display a distinct alteration in methionine utilization that affects their broader metabolic pathways. Most cancer cell lines are unable to proliferate when methionine is replaced with homocysteine, whereas non-cancerous cells do not exhibit this dependency. This pronounced reliance on exogenous methionine, scientifically termed methionine stress sensitivity or the Hoffman effect, reflects the intricate relationship between methionine availability and cancer cell viability [ 370 ]. Furthermore, in various animal models, there has been a compelling suggestion of a correlation between dietary intake of methionine and the associated risk of developing cancer, which underscores the importance of nutritional factors in cancer etiology. Notably, studies in rats with Walker-256 carcinosarcoma that were fed a methionine-deficient diet showed pronounced reductions in tumor growth, suggesting the potential of dietary manipulation as a therapeutic strategy [ 371 ]. In experiments involving Yoshida sarcoma in mice subjected to a similar methionine-restricted diet, researchers reported significant findings, including cell cycle blockade and marked tumor regression, thereby further substantiating the role of methionine in tumor biology [ 372 ]. In murine models bearing xenografted human solid tumors, including colon cancer, small cell lung cancer, and glioma, the use of a methionine-free dietary protocol sensitized cancer cells to chemotherapeutic agents, resulting in improved survival rates and effective inhibition of tumor growth [ 373 ]. In a noteworthy clinical trial, patients diagnosed with gastric cancer were administered methionine-depleting total parenteral nutrition in conjunction with the chemotherapeutic agent 5-fluorouracil for a duration of seven days prior to surgical resection, which revealed significant histopathological changes upon evaluation of the resected tumor specimens, including marked degeneration of tumor cells in comparison to control groups [ 374 ]. Conversely, it is essential to recognize that methionine, in conjunction with other nutrients such as folate, choline, betaine, and various B vitamins, plays an integral role in one-carbon metabolism, which in turn influences the synthesis of critical substrates necessary for DNA methylation processes, thereby regulating gene expression in a complex and interconnected manner [ 375 ].

The empirical evidence discussed here highlights the potential risks of a diet entirely devoid of methionine, despite claims of its anticancer properties, for which supporting data remain limited. It is important to emphasize that, in the context of oncological diseases, not only the intake of individual amino acids but also the source of consumed proteins plays a critical role. A comprehensive systematic review conducted by Alzahrani et al. in 2022 rigorously examined a broad range of studies evaluating the association between dairy-derived protein intake and prostate cancer risk. Among men who consumed more than 30 g of dairy protein per day, the findings revealed that each additional 20 g of daily dairy protein intake was associated with a 10% increase in prostate cancer incidence, a statistic warranting careful consideration. Notably, this association was not observed for proteins derived from other animal or plant sources, suggesting a distinct effect attributable specifically to dairy proteins [ 376 ]. Furthermore, a meta-analysis encompassing thirty-three cohort studies provided compelling evidence that the consumption of various dairy products, including milk, cheese, and butter, was associated with an elevated risk of the same oncological affliction, thereby reinforcing the need for caution among consumers of dairy [ 377 ]. Nevertheless, one plausible explanation for these alarming findings may not reside in the protein content per se, but rather in the substantial calcium content found in dairy products. Numerous epidemiological studies have consistently demonstrated a positive correlation between high calcium intake and the risk of developing prostate cancer, thus complicating the narrative surrounding dairy consumption. In the realm of colorectal cancer, empirical evidence has illustrated that a dietary shift from red meat-based protein sources to those derived from plants is associated with a diminished risk of incidence, highlighting the importance of protein source in cancer prevention strategies [ 378 ]. In the realm of colorectal cancer, empirical evidence has illustrated that a dietary shift from red meat-based protein sources to those derived from plants is associated with a diminished risk of incidence, highlighting the importance of protein source in cancer prevention strategies [ 379 ]. Conversely, a thorough analysis encompassing eight systematic reviews has revealed that a higher total protein intake does not correlate with an increased risk of colorectal and breast cancer, which challenges the prevailing assumptions regarding protein consumption. Additionally, similar patterns of correlation were observed for prostate, ovarian, and pancreatic cancers. However, it is crucial to note that the evidence supporting these findings remains insufficient to draw definitive conclusions [ 380 ].

These aggregated data suggest that although the source of dietary protein may influence cancer risk, the total quantity of protein consumed does not appear to be a major determinant. It is important to emphasize that individuals diagnosed with cancer often experience substantial weight loss and cachexia, conditions that significantly impair quality of life, reduce treatment efficacy, and diminish overall survival. Accordingly, ensuring adequate caloric intake and appropriate protein consumption is essential for supporting the health and well-being of these vulnerable patients during treatment [ 381 ].

Lipids

Among the most critical metabolic alterations associated with cancer is the heightened demand for fatty acids and cholesterol, which are pivotal for the structural integrity of cell membranes in rapidly proliferating cancerous cells, as well as for the synthesis of essential signaling molecules and the storage of energy reserves [ 382 ]. Whereas healthy cells predominantly acquire their lipid requirements from the bloodstream, cancer cells exhibit a remarkable propensity to de novo synthesize lipids, thereby facilitating their growth and survival in a nutrient-limited environment [ 383 ]. Research has demonstrated that, in certain cancer cell lines, fatty acids synthesized de novo may account for an astonishing 93% of the total lipid content in the cellular milieu, highlighting the metabolic adaptations these cells undergo [ 384 ]. An increased expression of the enzyme fatty acid synthase (FASN), which is responsible for the de novo synthesis of fatty acids, is commonly observed in invasive and aggressive forms of prostate cancer, especially when compared to benign lesions, thereby underscoring its potential role as a biomarker for cancer progression [ 385 , 386 ]. Furthermore, elevated levels of FASN expression have also been correlated with a poorer prognosis in patients diagnosed with pancreatic ductal adenocarcinoma, suggesting that lipid metabolism could serve as a prognostic indicator in cancer therapies [ 387 ]. Cancer cells exhibit a remarkable ability to alter the synthesis of enzymes integral to lipid metabolism, thereby modulating lipid composition through intricate processes such as fatty acid activation, desaturation, and elongation, which are critical for their survival and proliferation [ 388 ]. This comprehensive reprogramming of lipid metabolic pathways has been closely associated with a range of factors, including transcription factors, signaling cascades, and non-coding RNAs, which collectively orchestrate the complex regulation of lipid metabolism in the context of cancer biology [ 389 ].

Eicosanoids constitute a diverse group of lipid-based signaling molecules that play a pivotal role in numerous physiological processes. The primary substrate for eicosanoid synthesis is arachidonic acid, a polyunsaturated fatty acid, highlighting its importance in biochemical pathways [ 390 ]. A variety of compounds within this intricate family have been shown to exert significant effects on the proliferation, migration, and invasive capabilities of cancer cells, thereby influencing tumor dynamics [ 391 ]. For instance, prostaglandin E2, a member of the prostaglandin subfamily, has been shown in various studies to enhance tumor growth and increase tumor invasiveness, while concurrently promoting angiogenesis and modulating the surrounding tumor microenvironment [ 392 ]. In contrast, leukotriene B4, derived from the leukotriene subfamily, appears to predominantly regulate tumor progression through mechanisms primarily related to immune modulation, thereby affecting the overall tumor landscape [ 393 ]. Conversely, research using mouse models subjected to lung cancer transplantation has revealed that prostaglandin D2 exhibits tumor-suppressing effects; interestingly, the absence of its receptor has been associated with enhanced angiogenesis and increased tumor growth [ 394 ].

Additionally, dietary lipids have been shown to influence the intricate processes underlying cancer formation. Omega-3 fatty acids have been hypothesized to confer protective effects against the development of various cancers, and they are recognized for their anti-inflammatory properties, their stabilizing influence on the insulin receptor, their ability to promote analgesia through beta-endorphins, and their role in regulating hemostasis [ 395 ]. A comprehensive analysis by Lee et al. evaluating 57 meta-analyses comparing fish or omega-3 fatty acid consumption with cancer risk found that only 15 studies yielded statistically significant results. Notably, the evidence linking omega-3 fatty acid intake to breast cancer, hepatocellular carcinoma, prostate cancer, or brain tumors was found to be relatively weak and inconclusive [ 396 ]. Conversely, a ketogenic diet, characterized by the exclusive consumption of fats and proteins while minimizing carbohydrate intake, appears to have a beneficial effect when combined with cancer therapeutic modalities, as evidenced by preclinical studies [ 397 ]. This dietary regimen has been shown to enhance the efficacy of radiotherapy in the treatment of neoplasms and provides a protective mechanism against radiation-induced damage to healthy tissues [ 398 ]. In murine models of neuroblastoma, it has also been shown to impact chemotherapy outcomes. The integration of metronomic cyclophosphamide with a ketogenic diet resulted in significant tumor regression [ 399 ]. Furthermore, it enhanced the sensitivity of murine pancreatic tumors to the cytotoxic effects of a triple chemotherapy regimen comprising gemcitabine, nab-paclitaxel, and cisplatin. The synergistic effects of the ketogenic diet combined with chemotherapy were associated with a deceleration of tumor growth and an extension of survival compared to chemotherapy administered in isolation [ 400 ]. These favorable outcomes attributed to the ketogenic diet are elucidated by reductions in blood glucose concentrations, a metabolic shift toward energy acquisition from ketone bodies, modulation of amino acid metabolism, alterations in signaling molecules, and the expression of specific genetic markers [ 401 ]. Notwithstanding preclinical evidence of the ketogenic diet’s anticancer effects, clinical findings remain inconclusive. Urzì and colleagues have synthesized the results of seven clinical trials that examined the effects of the ketogenic diet on patients diagnosed with breast cancer. As of the time of this review’s composition, none of these trials have yielded definitive results affirming the superiority of the ketogenic diet [ 402 ]. Most critically, a systematic review and prospective assessment within the EPIC-Heidelberg Cohort employing an iso-caloric substitution model revealed that an increased proportion of animal protein at the expense of carbohydrates and fats in dietary energy intake was associated with heightened cardiovascular mortality risk [ 403 ]. In light of the aforementioned data, it is imperative to underscore that the ketogenic diet, when considered as an adjunct intervention during oncological therapies, lacks robustly established guidelines and necessitates further investigation. The manner of food preparation is equally significant in this context. Repeated heating of vegetable oils used for frying at elevated temperatures can lead to the formation of various deleterious compounds, including polycyclic aromatic hydrocarbons (PAHs). These compounds are recognized as carcinogens, with the potential to form DNA adducts, thereby initiating mutations that may serve as precursors to cancer transformation. They have been implicated in the pathogenesis of several malignancies, including lung, breast, colorectal, and prostate cancer [ 404 ].

Carbohydrates

In 1920, the distinguished biochemist Otto Warburg made a significant observation about the metabolic processes of cancer cells, noting that these cells preferentially utilize glucose via a mechanism known as anaerobic lactate fermentation, despite abundant oxygen in their environment. This phenomenon presents a paradox, particularly when one considers that aerobic phosphorylation, which occurs in the presence of oxygen, is a far more efficient process that yields considerably more energy. This metabolic behavior has since been referred to as the Warburg effect, a term that encapsulates the essence of his findings [ 405 ]. Despite the extensive body of research devoted to understanding the underlying mechanisms and implications of this effect, a comprehensive elucidation of its function remains elusive. It is hypothesized that the Warburg effect is intricately linked to the rapid energy demands of proliferating tumor cells, facilitating not only enhanced cellular biosynthesis but also the modulation of cell signaling pathways through ROS and alterations in chromatin structure, fostering immune evasion, and leading to the acidification of the tumor microenvironment, which ultimately disrupts the architecture of surrounding healthy tissues [ 406 ]. In recent years, the development of small-molecule inhibitors that specifically target the enzymes involved in glycolysis, thereby obstructing the utilization of glucose as a primary energy source, has emerged as a promising avenue for innovative cancer therapies [ 407 ]. The phenomenon of enhanced glucose metabolism is a distinctive hallmark often observed in tumor cells undergoing rapid proliferation. The identification and subsequent understanding of this metabolic characteristic have paved the way for significant advancements in medical imaging techniques, notably leading to the development of positron emission tomography (PET). This sophisticated imaging modality utilizes isotope-labeled 18-fluorodeoxyglucose, or FdG, which preferentially accumulates in areas where tumor foci are present, thus facilitating the identification and detection of distant metastases in patients diagnosed with cancer [ 408 ]. In response to their heightened energy demands, cancer cells exhibit an increased capacity for glucose uptake, which is achieved through the upregulation of glucose transport proteins, particularly GLUT1, underscoring a direct correlation between heightened GLUT1 expression and a greater degree of malignancy, as well as an enhanced potential for tumor metastasis [ 409 ]. The strategic inhibition of these glucose transporters using specific inhibitors has emerged as a compelling target in the ongoing development of novel cancer therapeutic strategies [ 410 ]. Furthermore, glucose and its associated metabolic pathways are not only pivotal for sustaining cellular proliferation but also play a critical role in thwarting programmed cell death (apoptosis), while simultaneously facilitating angiogenesis and the dissemination of cancer cells to distant sites, thereby contributing to metastasis [ 411 ]. In addition to their metabolic roles, saccharides in the human organism are intricately involved in the biochemical process of glycosylation. This essential biological process encompasses the intricate, multifaceted mechanism of linking saccharide molecules, commonly referred to as glycans, to various proteins and lipids, thereby affecting numerous physiological functions and cellular interactions [ 412 ]. In the context of neoplastic cells, it is observed that the process of glycosylation, which refers to the attachment of carbohydrate moieties to proteins or lipids, is executed aberrantly, leading to significant deviations when compared to the glycosylation patterns exhibited by healthy, non-cancerous cells. Such modifications in glycans’ profiles can play a pivotal role in modulating intercellular interactions among cancer cells and in improper adhesion to the extracellular matrix, a critical component of tissue architecture. Consequently, these pathological changes culminate in a heightened propensity for cancer cells to dissociate from their neighboring counterparts, thereby enhancing their metastatic potential, which is quantitatively assessed in a myriad of studies [ 413 ]. Furthermore, the condition known as diabetes is intrinsically linked to an impairment in the metabolism of sugars, leading to a range of systemic complications. Specifically, Type I diabetes manifests as a result of an autoimmune-mediated destruction of pancreatic beta cells, which are responsible for the secretion of insulin, resulting in a profound deficiency of this crucial hormone. On the other hand, Type II diabetes is characterized by an escalating resistance to insulin action, prompting a compensatory increase in insulin synthesis by pancreatic beta cells, which ultimately leads to hyperglycemia and hyperinsulinemia, followed by progressive dysfunction of insulin secretion [ 414 ]. It is imperative to note that both diabetes and the resultant state of hyperglycemia are recognized as significant risk factors for the development of various malignancies, including but not limited to pancreatic, hepatic, colorectal, breast, bladder, and endometrial cancers [ 415 ]. The underlying mechanism that elucidates this complex phenomenon involves a multifaceted interplay of factors, including, but not limited to, genetic predisposition, obesity, chronic inflammatory states, oxidative stress, elevated blood glucose levels, hyperinsulinemia, and the administration of specific oral diabetic pharmacological agents [ 416 ]. For instance, many cancer types are characterized by pronounced overexpression of the insulin receptor (IR), a critical component of cellular signaling pathways. The condition of hyperinsulinemia, which is commonly associated with type II diabetes as well as obesity, triggers the activation of the insulin receptor, leading to a cascade of metabolic events involving key molecules such as phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), and the mammalian target of rapamycin (mTOR), thereby facilitating uncontrolled cellular proliferation and setting the stage for the progression towards carcinogenesis [ 417 ]. The role of specific carbohydrates within the intricate metabolic pathways of cancer cells is undeniably vital; however, it is equally compelling to explore their implications as dietary components in the context of cancer development. Dietary fibers, which encompass a diverse array of substances derived from plant sources, are characterized by their resistance to digestion in the human gastrointestinal system, making them critical to the study of nutrition and health. These food fibers can be systematically categorized by structural composition into several types, including non-starch polysaccharides such as cellulose, hemicellulose, and pectin, as well as resistant starches and oligosaccharides that also exhibit resistance to enzymatic digestion [ 418 ]. These valuable fibers are predominantly sourced from a variety of food items, including, but not limited to, vegetables, fruits, legumes, whole-grain products, and cereals such as rice and groats, all of which contribute significantly to human dietary intake. The multifaceted properties of dietary fibers elucidate the mechanisms through which they confer various health benefits, underscoring their importance in a balanced diet. Insoluble dietary fibers, which consist of components like cellulose, hemicellulose, and lignin, serve to increase stool volume while simultaneously expediting the transit time of contents through the intestinal tract, thereby reducing the duration of contact between carcinogenic substances present in digested food and the delicate surface of the intestinal lining [ 418 , 419 ]. Conversely, the fraction of soluble fibers, characterized by their viscous and gel-forming properties, including inulin, resistant starches, and various oligosaccharides, undergoes complex bacterial fermentation in the colon, leading to myriad biochemical transformations. The resultant short-chain fatty acids that are synthesized during this fermentation process exhibit noteworthy properties that modulate the immune system, effectively reducing the inflammatory response while simultaneously exerting a beneficial influence on the metabolism of lipids and glucose [ 420 , 421 ]. Furthermore, it is important to note that whole grains and various fruits are rich in phenolic acids, compounds that have been extensively researched and found to possess significant anti-inflammatory properties [ 422 ]. The unique viscous and gel-forming characteristics of soluble fibers impede and delay carbohydrate absorption, thereby resulting in a marked decrease in postprandial glucose excursions [ 423 ]. It is particularly noteworthy that findings from prospective cohort studies have consistently demonstrated that a dietary regimen high in insoluble cereal dietary fibers is significantly associated with a reduced risk of developing diabetes. However, it is crucial to note that no such evidence has been established for diets predominantly rich in soluble fiber [ 424 ]. In addition, a comprehensive systematic review and meta-analysis focusing on dietary fiber has revealed compelling evidence that increased dietary fiber intake is associated with a diminished risk of pancreatic cancer, with no discernible association with either soluble or insoluble fiber [ 425 ]. In experimental models utilizing murine subjects, the incorporation of both soluble and insoluble dietary fibers has been demonstrated to significantly inhibit the activity of bacterial beta-glycosidase, a key enzyme implicated in various metabolic processes, and this inhibition has been shown to confer a protective effect against the development of mammary adenocarcinoma tumorigenesis, which is presumably attributable to alterations in the metabolism of estrogen [ 426 ]. After reviewing eleven comprehensive meta-analyses, Hu et al. (2023) concluded that dietary fiber provides extensive protective benefits against a wide range of malignancies, including gastrointestinal cancers such as colorectal, gastric, and esophageal cancers; gynecological cancers such as breast, endometrial, and ovarian cancers; and cancers of the pancreas, prostate, and kidneys. The term “sugars” commonly refers to simple carbohydrates, including monosaccharides such as glucose, galactose, and fructose, and disaccharides such as sucrose, lactose, and maltose, all of which play essential roles in human metabolism. Increased consumption of these sugars has been closely associated with the development and progression of numerous metabolic diseases, including obesity, type 2 diabetes, and cardiovascular disorders, which represent major public health challenges [ 427 ]. A comprehensive and extensive cohort study has conclusively demonstrated that an elevated intake of dietary sugars is significantly correlated with an increased overall risk for developing various types of cancer, with a particular emphasis on breast cancer, and this correlation has been shown to be independent of any weight gain that may typically accompany such dietary habits [ 428 ]. It is imperative to understand that the absence of a sweet flavor profile in a particular food item does not necessarily indicate that the product is sugar-free. The term “added sugars” refers specifically to sugars added during the manufacturing processes of highly processed foods, primarily to enhance their overall palatability and flavor. Research has consistently linked increased consumption of these added sugars to a wide range of adverse health outcomes, with significant implications for public health and individual dietary practices [ 429 ]. In the comprehensive research conducted by Epner et al., the authors demonstrate a significant association between high consumption of added sugars and an increased risk of developing various cancers, along with a heightened likelihood of mortality, with breast cancer identified as particularly concerning. The study also reports a notable correlation between added sugar intake and rising colorectal cancer incidence, underscoring the potential dangers of excessive sugar consumption. This relationship may be explained by the strong link between high sugar intake and obesity, a well-established risk factor for multiple cancers. Additionally, the study highlights the pro-inflammatory potential of added sugars, their harmful effects on metabolic pathways involving glucose and fructose, and the broader biochemical consequences of excessive intake. The investigation further emphasizes the negative impact of added sugars on immune function, suggesting that such dietary patterns may impair immune responses and increase susceptibility to disease [ 430 ]. Figure 5 illustrates the intricate relationship between macronutrients and the epigenome of cancer cells.

Dietary modulation of tumor immunometabolism and epigenetics

Dietary factors are increasingly recognized as important modulators of the tumor microenvironment (TME). By influencing both systemic and local metabolite availability, diet can alter tumor-cell metabolic programs and the metabolic–epigenetic states of tumor-infiltrating immune cells [ 431 , 432 ]. These effects occur primarily through two converging mechanisms. First, they provide or deplete substrates and cofactors, such as acetyl-CoA, SAM, and α-ketoglutarate, which directly regulate chromatin-modifying enzymes. Diet-induced changes in the gut microbiome lead to the production of bioactive metabolites, including short-chain fatty acids (SCFAs), which serve as distal epigenetic regulators [ 433 ].

Existing interventional trials are determining whether specific dietary strategies, such as high-fiber diets, fermentation substrates, or amino acid-restricted diets, can improve the efficacy of immunotherapy. Preliminary translational studies demonstrate a modification in the tumor-infiltrating T-cell metabolic and epigenetic signatures, which, in certain subgroups of the patient population, correlate with improved clinical benefit [ 434 ]. Dietary patterns rich in fermentable fiber, plant-derived polyphenols, and unsaturated fats, such as the Mediterranean diet and, in some studies, ketogenic diets, have been associated with changes in tumor metabolism and modulation of T-cell function [ 435 ].

Epinutritional nutrients also interact directly with cellular epigenetic machinery. By providing or inhibiting specific substrates and cofactors, they modulate the activity of key epigenetic enzymes, including DNMTs, Ten-eleven translocation (TET) proteins, and various histone-modifying regulators. These interactions can alter DNA methylation patterns and histone post-translational modifications, such as acetylation, methylation, and hydroxymethylation, thereby contributing to chromatin remodeling and reshaping transcriptional programs that regulate tumor cell growth, survival, and apoptosis. Through their effects on intracellular metabolic networks and their interactions with the intestinal microbiome, epinutrients also influence the production of bioactive metabolites, including SCFAs, which function as secondary epigenetic modulators that link dietary inputs to metabolic and transcriptional pathways [ 436 ].

Recent studies suggest that high-fiber dietary patterns can modulate the composition and function of the gut microbiome, leading to increased production of SCFAs, in particular, butyrate and propionate. These microbiome shifts have been associated with improved responses to immunotherapies, most notably immune checkpoint blockade (ICB). Elevated SCFA levels have also been indicated to enhance CD8⁺ T cell activities and the stronger antitumor effects of immunotherapy [ 437 ]. Butyrate, a prototypical SCFA produced by bacterial fermentation of dietary fiber, serves as both an energy substrate and an inhibitor of class I and II histone deacetylases (HDACs). Through this dual activity, butyrate promotes histone acetylation and chromatin remodeling, hence activating tumor growth-suppressive, apoptosis-inducing, and antitumor immune-modulating transcription programs [ 438 ].

Butyrate enhances chromatin accessibility in CD8⁺ T cells by inhibiting class I and II HDACs at cytokine and cytotoxic effector gene loci. This inhibition promotes the upregulation of key effector genes, including IFN-γ, TNF, granzyme B (GzmB), and IL-2, thereby strengthening T cell cytotoxic function. Butyrate stimulation also drives the differentiation of CD8⁺ T cells into effector memory (T_EM) and central memory (T_CM) subsets, accompanied by increased expression of CD44, CD62L, and T-bet. These molecular and phenotypic changes enhance intratumoral T cell infiltration, increase cytotoxic activity against tumor cells, and improve long-term immune surveillance of tumor growth [ 439 ]. Within the intestinal epithelium, butyrate serves as a preferred energy source for oxidative metabolism and contributes to epithelial homeostasis. However, in tumor contexts, butyrate can exert antiproliferative effects and regulate the expression of genes controlling cell-cycle progression and apoptosis [ 440 ]. These findings indicate that the functions of butyrate and other SCFAs in the TME are highly contingent on the target cell type, its metabolic state, and the site-specific levels of these metabolites. Under some conditions, they act as supportive fuels, whereas in others, they function as epigenetic regulators with antitumor activity [ 433 ].

Dietary polyphenols also exert significant epigenetic effects. Resveratrol, one of the most extensively studied compounds in this group, acts beyond its antioxidant and anti-inflammatory properties to directly modulate epigenetic function in immune and cancer cells. It alters chromatin accessibility by inhibiting DNMT activity, modulating histone acetyltransferases (HATs), and affecting both DNA methylation and histone acetylation states [ 441 ]. These epigenetic changes reprogram antitumor gene expression across pathways involved in the cell cycle, apoptosis, DNA repair, and antitumor signaling, thereby suppressing cancer cell growth and enhancing antitumor immunity in preclinical models [ 442 ]. Resveratrol also reconfigures epigenetic networks in immune cells, strengthening their capacity to sustain antitumor immune responses. This dual activity underscores its promise as an epinutrient for cancer prevention and therapy [ 443 ].

Several studies have shown that nutritional phytochemicals, such as resveratrol, EGCG, curcumin, and quercetin, may act by upstream metabolic reprogramming [ 444 ]. By regulating NAD⁺/NADH, acetyl-CoA, and other metabolic cofactors, they influence the activity of epigenetic enzymes such as sirtuins (SIRT1–7) and HATs. This regulation remodels chromatin structure, regulates the accessibility of gene loci, and reprograms transcription, thereby enhancing effector functions, cell differentiation, and antitumor immunity in tumor microenvironment immune cells [ 432 , 445 ]. Resveratrol has been shown to epigenetically modulate histone methylation in breast cancer cells by downregulating EZH2 , thereby reducing levels of the suppressive mark H3K27me3. This change reactivates tumor suppressor genes such as BRCA1 , p53 , and p21 CIP1 , indicating its role in restoring antitumor pathways through chromatin remodeling [ 446 ]. Furthermore, such phytochemicals indirectly regulate the expression of genes associated with T and NK cell cytokine production, migration, and cytotoxic activity by modulating cellular metabolic processes and signaling cascades, thereby establishing a direct link between nutritional status and epigenetic regulation of antitumor immunity through gene expression [ 432 ].

In the study by Wang et al., micronutrients involved in the one-carbon metabolism pathway, such as folate, methionine, and choline, were shown to be critical determinants of intracellular SAM levels. SAM serves as the essential cofactor for all methylation reactions, and cellular methylation potential is defined by the SAM-to-S-adenosylhomocysteine (SAM/SAH) ratio. Accordingly, alterations in the availability or utilization of these micronutrients can modulate the activity of SAM-dependent epigenetic enzymes, including DNMTs and HMTs. This regulation affects not only global DNA and histone methylation patterns but also methylation at specific gene loci, thereby reshaping transcriptional programs that govern tumor cell survival, proliferation, and immune function [ 447 ]. Disruption of the one-carbon metabolism pathway profoundly influences the epigenetic reprogramming of melanoma immune cells, with direct consequences for T cell differentiation. Methylation or demethylation at the T-bet and FoxP3 promoters determines CD4⁺ T cell fate, directing differentiation toward either a pro-inflammatory, antitumor Th1/CTL phenotype or an immunosuppressive regulatory T cell (Treg) phenotype [ 448 , 449 ]. In CD8⁺ T cells, methylation of cytokine genes such as interferon gamma (IFNG) and tumor necrosis factor (TNF) regulates cytotoxic function and the formation of long-term antitumor memory. Beyond T cells, the one-carbon pathway also governs macrophage polarization. Epigenetic modifications at genes such as iNOS and IL12 promote an M1 phenotype characterized by pro-inflammatory and antitumor activity, whereas methylation changes at loci including Arg1 and IL10 drive macrophages toward an M2 phenotype associated with immunosuppression and tumor promotion [ 435 ].

Recent evidence indicates that reprogramming of immune and cancer cell lipid metabolism within the tumor microenvironment is a critical mechanism underlying both the initiation of colorectal cancer and its capacity for immune evasion [ 450 ]. Tumor cells extensively remodel phospholipid, cholesterol, and fatty acid metabolic pathways to supply energy, generate membrane components, and support signaling networks. These alterations not only promote enhanced proliferation and survival of cancer cells but also indirectly modulate the function of antitumor immune cells [ 451 ]. For example, the accumulation of fatty acids and cholesterol in the tumor microenvironment may promote the activity and differentiation of myeloid-derived suppressor cells (MDSCs) and M2-polarized macrophages [ 452 ]. More specifically, acetyl-CoA derived from dietary lipids can modulate histone acetylation at genes regulating macrophage polarization and cytokine expression, thereby influencing localized immune responses against the tumor. These immunosuppressive cells secrete cytokines and inhibitory mediators that create a microenvironment limiting cytotoxic T-cell infiltration and activation. In addition, alterations in phospholipid composition and the accumulation of lipid peroxidation products induce oxidative stress and disrupt immune signaling cascades, thereby enabling epigenetic silencing of inflammatory and antitumor response genes [ 453 ]. Fatty acids and lipid-derived signaling molecules from dietary fat can also function as epigenetic regulators by modulating histone acetylation through acetyl-CoA availability and activating nuclear receptors that drive chromatin remodeling and gene regulation [ 454 ]. These processes reprogram gene expression programs in both tumor and immune cells. Furthermore, lipid metabolic reprogramming in cancer cells provides the energy and structural precursors required for proliferation and migration while generating signaling lipids that mediate tumor–immune cell interactions [ 451 ]. Conversely, pharmacological inhibition of lipid metabolic pathways (whether through small-molecule inhibitors or metabolic engineering) can reprogram the tumor immune microenvironment. Targeting cholesterol or fatty acid synthesis not only suppresses tumor growth and proliferation but also reduces the activity of immunosuppressive cells and enhances T-cell responses to ICB therapies [ 455 ]. Overall, these findings suggest that lipid metabolism is not merely a characteristic of cancer but also a promising therapeutic target for enhancing immunotherapy in colorectal cancer.

Oncometabolites generated through tumor-associated metabolic dysregulation, such as D-2-hydroxyglutarate (D-2HG) produced by IDH mutations, fumarate, and succinate, may inhibit α-ketoglutarate–dependent dioxygenases. Among the affected enzymes are TET DNA demethylases and Jumonji histone demethylases, whose inhibition results in DNA and histone hypermethylation and a preference for a closed, transcriptionally silent chromatin state [ 456 ]. These changes in chromatin remodeling, along with the silencing of genes involved in antigen presentation and T cell activation, significantly undermine antitumor immune responses. Furthermore, the levels of these oncometabolites and their ratios relative to α-ketoglutarate can be modulated by the gut microbiota, dietary interventions, and host metabolic status, highlighting these epigenetic pathways as promising and actionable therapeutic targets in cancer [ 457 ].

Single-cell multi-omics analyses have shown that nutritional interventions can coordinately reprogram the metabolic and epigenetic networks of tumor-infiltrating lymphocytes (TILs). This reprogramming modifies the cellular states of distinct T-cell subsets, including cytotoxic CD8⁺ T cells and helper CD4⁺ T cells. Chromatin profiling indicates that specific dietary interventions increase H3K27ac acetylation at enhancer elements of genes regulating activation and antitumor functions, while concurrently reducing repressive methylation at loci involved in antigen presentation and immune response pathways. These epigenetic alterations occur in parallel with shifts in T-cell glucose, fatty acid, and amino acid metabolism, thereby enabling TILs to function more effectively within the metabolically demanding tumor microenvironment [ 458 – 460 ]. Furthermore, evidence indicates that nutrient modulation alters T-cell energy reservoirs, biosynthetic capacity, and reprograms immune and cancer cell signaling networks. At the systems level, this reprogramming establishes a new balance between activating and inhibitory signals, thereby enhancing tumor sensitivity to immunotherapy. Diet, together with other environmental factors, becomes a significant driver that can reprogram metabolic and epigenetic networks in TILs, thereby playing a central role in shaping antitumor immune responses [ 431 ].

Nutritional interventions that modulate the gut microbiota have emerged as important regulators of antitumor immunity. High-fiber diets and supplement strategies that specifically enrich beneficial microbial groups increase the abundance of microbes with the potential to produce anti-inflammatory and epigenetically active metabolites, such as butyrate [ 461 , 462 ]. By inhibiting HDAC enzymes and modulating T-cell regulatory pathways, butyrate enhances systemic immune function and improves immunotherapy sensitivity [ 463 , 464 ]. For example, in mice receiving prebiotic or fiber-rich diets, the expansion of species such as Faecalibacterium prausnitzii and Akkermansia muciniphila correlates with increased intratumoral CD8⁺ T-cell infiltration [ 437 , 465 ]. Clinical observational studies of patients treated with ICI indicate that high-fiber diets correlate with greater microbiota diversity, dominance of SCFA producers, and improved therapeutic responses. In addition, several ongoing clinical trials are directly evaluating fiber supplementation, prebiotics, and dietary modulation in combination with immunotherapy, underscoring the current priority of this approach in clinical trial design [ 437 ].

Given the systemic nature of nutritional effects, the formulation of dietary supplements must be carefully tailored to timing, macronutrient balance, and the patient’s metabolic status, including age and comorbidities. These host-related factors profoundly influence the delivery, distribution, and metabolism of nutrients and their metabolites within the TME [ 431 , 466 ]. Although strong evidence and emerging translational findings support the role of diet in modulating cancer metabolism through epigenetic mechanisms, stringently designed clinical trials are still required to establish causality, optimize dietary strategies, and determine appropriate criteria for patient selection [ 434 ].

Personalized nutritional epigenetics for cancer prevention and therapy

Precision oncology emphasizes the importance of inter-individual variability in both cancer risk and therapeutic outcomes, highlighting the need for nutritional strategies tailored to each individual’s genetic and epigenetic profile [ 467 ]. Nutritional epigenetics, or nutri-epigenomics, presents a mechanistic framework in which dietary components exert effects through DNA methylation, histone modification, and modulation of the non-coding RNAs. These epigenetic processes not only prime cellular and immune responses but are also extremely heterogeneous from person to person and reflect associated genetic, epigenetic, and metabolic heterogeneity [ 436 ].

This individual heterogeneity occurs due to both germline variants, for example, polymorphisms in the MTHFR gene that alter folate metabolism, and somatic mutations, such as alterations in DNMT3A or TET2 that influence the post-transcriptional remodeling of hematopoietic cells [ 468 – 471 ]. For instance, folate supplementation exerts variable effects on DNA methylation depending on the MTHFR genotype, highlighting the need for genotype-directed nutritional interventions [ 472 ]. Similarly, allelic variations in the vitamin D receptor (VDR) have been associated with differential cancer risk and may modify the epigenetic consequences of vitamin D-dependent chromatin remodeling. These genetic interactions with nutrients demonstrate that uniform dietary recommendations aimed at influencing epigenetic modifications are unlikely to be effective; instead, stratifying patients by both genotype and epigenotype is essential [ 473 , 474 ]. This series of studies provides further evidence for patient stratification based on modifiable epigenetic states and for tailored dietary approaches designed to reprogram gene expression and inflammatory pathways [ 475 , 476 ]. Several dietary bioactive molecules demonstrate consistent epigenetic activity with substantial translational potential. Sulforaphane (SFN), an isothiocyanate present in cruciferous vegetables, inhibits HDACs and modulates both histone acetylation and DNA methylation at regulatory regions of tumor suppressor genes. Preliminary human trials using broccoli sprout extracts have provided encouraging molecular evidence, suggesting the potential for diet-mediated epigenetic modification in patients [ 477 , 478 ].

Similarly, EGCG intersects with DNMTs and histone-modifying enzymes, with robust preclinical epigenetic evidence and growing clinical data across multiple malignancies [ 479 , 480 ]. For such bioactive compounds, the biological outcome is governed not only by tumor-intrinsic factors, such as chromatin accessibility and cofactor availability, but also by host-related variables, including genotype, microbiome-dependent precursor metabolism, and baseline nutrient status [ 481 ]. Large cohort studies and diet–disease association analyses consistently report a reduced incidence of certain cancers with higher consumption of dietary fiber, cruciferous vegetables, and carotenoid-rich foods. Subgroup analyses and gene–environment interactions indicate that these associations are often stronger or observed exclusively in individuals with specific genetic or epigenetic features [ 482 ].

Early intervention trials using sulforaphane-enriched extracts and concentrated polyphenol supplements have demonstrated that surrogate molecular endpoints, such as HDAC activity and locus-specific DNA methylation, are modifiable, with occasional indications of clinical benefit. Establishment of causality, defining optimal dosing regimens, and validating the durability of these effects will require adequately powered randomized trials that incorporate molecular patient stratification [ 478 , 483 ].

Personalized nutritional epigenetics research has expanded significantly in recent years through large epidemiologic studies, biomarker identification, and early-phase clinical trials. These investigations have yielded significant findings linking nutrient intake to reduced cancer risk and improved survival outcomes. For example, a 2025 NHANES-based study identified that higher serum concentrations of α-carotene, β-carotene, lycopene, and lutein/zeaxanthin were significantly associated with lower all-cause mortality among cancer survivors [ 484 ]. These results highlight the potential role of carotenoids not only as nutritional biomarkers but also as surrogate indicators of cancer survivorship.

Likewise, higher dietary fiber intake has consistently been associated with a reduced incidence of several cancers, most prominently pancreatic and colorectal cancers [ 485 , 486 ]. Studies also indicate that whole-grain consumption reduces the risk of hepatocellular carcinoma, an effect most likely governed by metabolites generated by the microbiome, including SCFAs, which influence histone acetylation and the expression of inflammatory genes [ 487 , 488 ]. Mechanistically, these associations are biologically plausible; however, considerable heterogeneity in fiber type, food matrix, and study populations underscores the need for larger, better-controlled trials.

Advances in technology now enable patient-level prioritization of epigenetic dietary strategies. Single-cell epigenomics methods, including scATAC-seq and single-cell bisulfite or methylation assays, reveal heterogeneity in chromatin states within tumors and in the extent of immune infiltration, thereby identifying cell populations most likely to undergo epigenetic modifications in response to metabolites or cofactors [ 489 , 490 ]. Furthermore, machine-learning-based artificial intelligence platforms that integrate dietary intake, microbiome composition, metabolomic profiles, and tumor epigenomic data can predict individual responses to metabolites and prioritize interventions. For instance, such platforms may identify patients most likely to benefit from high-fiber diets that enhance the production of butyrate and other SCFAs, potentially improving epigenetic regulation and immune function [ 491 , 492 ]. Computational multi-omics approaches provide evidence that supports the development of testable hypotheses for personalized nutritional interventions.

From the clinical perspective, an evidence-based approach to personalized nutritional epigenetics can be charted in several steps. First, baseline molecular profiling should be conducted, including germline genotyping panels for critical metabolic and epigenetic genes, epigenomic marks from tumor-adjacent tissues, and comprehensive microbiome and metabolome assessments. Second, a computational prioritization phase employs verified artificial intelligence approaches to predict the most probable nutritional interventions to regulate target epigenetic marks in predicted responders. Third, biomarker-directed interventions are implemented; for example, a high-fiber diet with prebiotics to enhance butyrate production in predicted responders, particularly in patients with repressive tumor histone marks that are sensitive to HDAC inhibition. Finally, longitudinal molecular monitoring is performed, encompassing locus-specific DNA methylation, histone modifications, and immune phenotypes, thereby enabling adaptive optimization of interventions. Successful implementation of this approach will require standardization of assays, reproducible biomarkers, and prospective evaluation in randomized trials in molecularly stratified patient populations [ 492 , 493 ].

Before the widespread clinical implementation of personalized nutritional epigenetics, several important challenges must be addressed. For example, genetic heterogeneity in micronutrient metabolism, such as the MTHFR C677T polymorphism and its effect on folate status and colorectal cancer risk, underscores the importance of accounting for both genetic and population-level variation when designing interventions [ 494 ]. In addition, the challenges of dietary adherence and the potential for adverse effects in specific subgroups underscore the need to incorporate reliable biomarkers and robust safety monitoring [ 495 ]. Finally, the practical application of rigorously planned clinical trials based on molecular data and predefined endpoints for epigenetic research is consistent with current efforts to integrate epigenetics into pharmacology and therapeutic development [ 496 ].

Collectively, individualizing nutrition based on genetic predisposition, single-cell epigenomic profiles, metabolomic states, and microbiome signatures has the potential to be a noninvasive complement to established approaches for cancer prevention and therapy. Realizing this potential will require rigorously designed clinical trials that incorporate single-cell epigenomic diagnostics [ 489 ], metabolome profiling, and machine-learning predictive algorithms [ 492 ], while carefully accounting for microbiome effects on immunotherapy efficacy [ 437 ]. These trials should incorporate molecular biomarkers, epigenetic signatures, and microbiome dynamics to guide interventions and evaluate therapeutic outcomes. If demonstrated to be effective, personalized nutritional epigenetics may become a scalable, complementary strategy for cancer prevention and treatment, addressing a critical gap that current personalized medicine has yet to fully address.

Conclusion

Dietary patterns rich in fruits, vegetables, whole grains, phytochemical-dense foods, and marine-derived fatty acids consistently affect epigenetic pathways relevant to carcinogenesis, a finding supported by mechanistic and epidemiologic data. Fermentable fibers provide an additional route of action by promoting microbial production of short-chain fatty acids, such as butyrate, which influence histone acetylation, immune gene expression, and antitumor immunity. These mechanisms overlap with targets of pharmacologic epigenetic agents, suggesting potential complementarity. A developing field is personalized nutritional epigenetics, which links dietary recommendations to an individual’s molecular profile, including germline variants that affect nutrient metabolism, tumor-specific epigenomic features, microbiome composition, and circulating metabolites. Computational prediction models, single-cell epigenomic methods, and machine-learning frameworks may help identify patients who are more likely to benefit from high-fiber diets, phytochemical-rich regimens, or targeted micronutrient adjustments. Such strategies require biomarker-guided implementation and longitudinal monitoring of DNA methylation at relevant loci, histone marks, and immune parameters.

Acknowledgements

None.

Abbreviations

Arginine Deiminase–Polyethylene Glycol 20

Acute Lymphoblastic Leukemia

Activating Molecule in Beclin-1–Regulated Autophagy

Acute Myeloid Leukemia

Adenosine Monophosphate

AMP-Activated Protein Kinase

Transcription Factor AP-2 Alpha

Acute Promyelocytic Leukemia

Aplasia Ras Homolog Member I

Aryl Hydrocarbon Receptor Nuclear Translocator

Argininosuccinate Lyase

Argininosuccinate Synthetase 1

Autophagy-Related Gene

Autophagy-Related Protein 2B

Autophagy-Related Protein 4A

Autophagy-Related Protein 4D

Autophagy-Related Protein 5

Autophagy-Related Protein 7

Autophagy-Related Protein 8/Microtubule-Associated Protein 1 Light Chain 3

Autophagy-Related Protein 9

Autophagy-Related Protein 12

Autophagy-Related Protein 16-like 1

Adenosine Triphosphate

All-Trans Retinoic Acid

B-cell Acute Lymphoblastic Leukemia

BCL2-Associated Transcription Factor 1

BCL-2–Like Protein 10

B-cell Lymphoma 2

Brain Metastasis

Body Mass Index

B-lymphoma Mo-MLV Insertion Region 1

Bcl-2/Adenovirus E1B 19 kDa-Interacting Protein 3

Brahma-Related Gene 1

Brahma (SMARCA2)

B-cell Translocation Gene 1

B-cell Translocation Gene 3

CREB-Binding Protein

Clear Cell Renal Cell Carcinoma

Chromodomain Helicase DNA-Binding Protein 5

Chronic Lymphocytic Leukemia

Cellular Myelocytomatosis Oncogene

Chronic Myeloid Leukemia

Cytosine–Phosphate–Guanine

Caloric Restriction

Dishevelled-Binding Antagonist of β-Catenin 3

Docosahexaenoic Acid

Dicer 1, ribonuclease III

3,3′-Diindolylmethane

Deoxyribonucleic Acid

DNA Methyltransferase

DNA Methyltransferase 1

DNA Methyltransferase 3A

DNA Methyltransferase Inhibitor

Embryonic Ectoderm Development Protein

Epigallocatechin Gallate

Extracellular Leucine-Rich Repeat and Fibronectin Type III Domain–Containing Protein 2

Epithelial-to-Mesenchymal Transition

Eicosapentaenoic Acid

Endothelial PAS Domain Protein 1

Epithelial Cell Adhesion Molecule

Eight-Twenty-One (RUNX1–ETO fusion)

Enhancer of Zeste Homolog 2

Flavin Adenine Dinucleotide

Focal Adhesion Kinase Family-Interacting Protein of 200 kDa

Fms-like Tyrosine Kinase 3 Internal Tandem Duplication

Forkhead Box Protein O1

Euchromatic Histone-Lysine N-Methyltransferase 2

GATA-Binding Protein 3

Glucose Transporter Type 1

Glutathione S-transferase Pi 1

Histone 2 A / Histone 2B

Histone 3 / Histone 4

Histone H3 Lysine 4 Mono/Di-Methylation

Histone H3 Lysine 9 Acetylation

Histone H3 Lysine 9 Mono/Di/Tri-Methylation

Histone H3 Lysine 18 Acetylation

Histone H3 Lysine 27 Trimethylation

Histone Methylation Sites

Histone H3 Serine 10 Phosphorylation

Histone Acetyltransferase

Hepatocellular Carcinoma

Histone Deacetylase

Histone Deacetylase Isoforms

Histone Deacetylase Inhibitor

Histone Demethylase

Hypoxia-Inducible Factor

Hypoxia-Inducible Factor-1 Alpha

Hypoxia-Inducible Factor-1 Beta

High Mobility Group Box 1

Histone Methyltransferase

Hematopoietic Progenitor Cell Antigen 1

Hypoxia Response Element

Human Colon Adenocarcinoma Cell Line

Inhibitor of DNA Binding 4

Isocitrate Dehydrogenase 2

Insulin-Like Growth Factor 1

Interferon Regulatory Factor 2

Jumonji Domain-Containing Histone Demethylase 3A

Jumonji C Domain

Jumonji Domain-Containing Protein D3

Lysine Demethylase

Lysine Demethylase 3B

Lysine Demethylase Inhibitor

Krüppel-Like Factor 4

Lysine Methyltransferase

Lysine Methyltransferase Inhibitor

Key Transcriptional Modulators

Microtubule-Associated Protein 1 Light Chain 3

Long Interspersed Nuclear Element-1

Leukemic Stem Cell

Lysine-Specific Demethylase 1

Monoamine Oxidase

Microtubule-Associated Protein 1 Light Chain 3 Alpha Variant 1

Myelodysplastic Syndrome

Melanoma Nuclear Protein 18

MicroRNA

MutL Homolog 1

Multiple Myeloma

Multiple Myeloma SET Domain Protein

Monocytic Leukemia Zinc Finger Protein

Messenger RNA

Nicotinamide Adenine Dinucleotide

Non-Coding RNA

Nicotinamide N-methyltransferase

Nucleophosmin 1

Nuclear Receptor-Binding SET Domain Protein 1

Nuclear Receptor-Binding SET Domain Protein 2

Non–Small Cell Lung Cancer

8-Oxoguanine DNA Glycosylase 1

Oral Squamous Cell Carcinoma

Ovarian Tumor–Initiating Cells

P300/CBP-Associated Factor

Polycomb Group

Polyethylene Glycol

Phosphoglycerate Kinase 1

Polyhomeotic Homolog 1

Phosphoinositide 3-Kinase

Prostatic Intraepithelial Neoplasia

Protein Phosphatase 2A

Polycomb Repressive Complex 1

Polycomb Repressive Complex 2

Post-Translational Modifications

Protein Tyrosine Phosphatase Non-Receptor Type 11

Ras-Related Protein Rab-5A

Retinoic Acid Receptor Beta

Ribonucleic Acid

Runt-Related Transcription Factor 1

Serum Amyloid A

S-Adenosylhomocysteine

S-Adenosyl Methionine

Satellite Alpha Sequence

Su(var)3–9, Enhancer-of-Zeste and Trithorax Domain

Sirtuin 1 / Sirtuin 3

SWI/SNF Related Matrix-associated Actin-dependent Regulator of Chromatin A2

SET and MYND Domain-Containing Protein 3

Sequestosome 1

Suppressor of Zeste 12 Protein

Switching Defective/Sucrose Non-Fermenting Complex

Chromosomal Translocation Between Chromosomes 4 and 14

Transcription Factor 21

Tumor Suppressor Candidate 3

Ubiquitin-Like Containing PHD and RING Finger Domains 1

Unc-51 Like Autophagy-Activating Kinase 1/2

Untranslated Region

Ubiquitously Transcribed Tetratricopeptide Repeat Protein X

UV Radiation Resistance Associated Gene

Voltage-Dependent Anion Channel 1

Vascular Endothelial Growth Factor

Von Hippel–Lindau Tumor Suppressor

WD Repeat Domain, Phosphoinositide Interacting 1

Wilms’ Tumor 1

Author contributions

Conceptualization: Ali Jafari. Project administration: Fatemeh Boroomand and Ali Jafari. Visualization: Elaheh Karimzadeh-Soureshjani and Daryoush Kiani-Shamsabadi. Supervision: Mohammad Amin Karimi and Ali Jafari. Writing– original draft: Fatemeh Boroomand, Elaheh Karimzadeh-Soureshjani, Daryoush Kiani-Shamsabadi, Fatemeh Farhang. Writing– review & editing: Helia Mardani, Mohammad Amin Karimi, Ali Jafari.

Funding

Not applicable.

Data availability

All relevant data are provided within the manuscript.

Declarations

Human ethics and consent to participate

Not applicable.

Statement on the Use of Artificial Intelligence (AI)

We acknowledge that this essay was edited and its writing style refined with the help of ChatGPT (GPT-5, OpenAI’s large-scale language generation model, used via the editGPT extension). The AI was not used to create the manuscript’s content or references; it was employed solely to enhance the language. All AI-assisted text was carefully reviewed, edited, and rewritten by the authors, who assume full responsibility for the article’s accuracy and substance.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s note

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

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Associated Data

Data Availability Statement

All relevant data are provided within the manuscript.