This review highlights the critical role of epigenetic regulation in nuclear receptor function, shedding new light on its influence over endocrine-related diseases. It provides a comprehensive analysis of how DNA methylation, histone modifications, RNA-based mechanisms, and chromatin remodeling govern nuclear receptor activity, ultimately affecting metabolic and hormone-driven disorders such as diabetes, thyroid disease, and hormone-dependent cancers.
Endocrine disorders affect millions worldwide, with conditions like breast cancer, osteoporosis, and thyroid dysfunction presenting significant public health challenges. Nuclear receptors, a class of proteins that mediate hormonal signaling, rely on tightly controlled gene expression to function correctly. However, aberrant epigenetic changes can disrupt this balance, leading to disease progression.
One of the key mechanisms explored in this article is DNA methylation, a process in which methyl groups are added to DNA, potentially silencing critical genes. This phenomenon has been linked to breast cancer, where hypermethylation of the BRCA1 gene correlates with increased tumor risk. Similarly, in osteoporosis, altered methylation of genes like RANKL and osteoprotegerin impacts bone density regulation.
Another crucial regulatory process is histone modification, which involves chemical changes to histone proteins that control DNA accessibility. Histone acetylation, for instance, enhances gene transcription, while deacetylation suppresses it. Nuclear receptors interact with coactivators and corepressors, influencing gene expression through modifications like H3K9 methylation and H3K27 trimethylation—both of which play pivotal roles in hormone receptor-driven cancers and metabolic diseases.
Beyond direct DNA and histone modifications, non-coding RNAs such as microRNAs (miRNAs) regulate nuclear receptor function. These small RNA molecules act as gene silencers, affecting receptors like the estrogen receptor (ER) in breast cancer and the glucocorticoid receptor (GR) in stress-related metabolic disorders. Disruptions in these RNA pathways have been implicated in endocrine-related cancers and metabolic syndromes.
With these insights, the authors also highlight emerging therapeutic strategies targeting epigenetic mechanisms. Treatments such as epigenetic drugs, gene editing technologies, and histone deacetylase inhibitors (HDAC inhibitors) hold promise for restoring proper nuclear receptor function. These novel interventions could revolutionize treatment approaches for hormone-related diseases, moving towards precision medicine that tailors therapies to an individual's unique epigenetic profile.
As the field of epigenetics continues to advance, understanding the complex interactions between nuclear receptors and their regulatory mechanisms is crucial. This review underscores the potential for epigenetic therapies to transform treatment strategies, paving the way for breakthroughs in combating endocrine-related diseases and improving patient outcomes worldwide.

Funding Information:
National Natural Science Foundation of China 82170865
National Natural Science Foundation of China 82370856
National Natural Science Foundation of China 32101029
Natural Science Foundation of Shandong Province, China ZR2020QB164
Shandong Province Medical and Health Science and Technology Development Project of China 202203060805
Shandong Province Medical and Health Science and Technology Development Project of China 202203060917
Taishan Scholars Project of Shandong Province, China tsqn202211365

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Reference
Xiaodong Sun, Epigenetic regulation of nuclear receptors: Implications for endocrine-related diseases and therapeutic strategies, Genes & Diseases, Volume 12, issue 4, 2025, 101481, https://doi.org/10.1016/j.gendis.2024.101481