Abdel-Rasol Mohammed A, El-Sayed Wael M
Department of Zoology, Faculty of Science, Ain Shams University, Abbassia, Cairo, 11566, Egypt.
Eur J Med Res. 2025 Sep 9;30(1):843. doi: 10.1186/s40001-025-03073-6.
Nuclear receptors (NRs) are a superfamily of ligand-activated transcription factors that regulate gene expression in response to metabolic, hormonal, and environmental signals. These receptors play a critical role in metabolic homeostasis, inflammation, immune function, and disease pathogenesis, positioning them as key therapeutic targets. This review explores the mechanistic roles of NRs such as PPARs, FXR, LXR, and thyroid hormone receptors (THRs) in regulating lipid and glucose metabolism, energy expenditure, cardiovascular health, and neurodegeneration. The therapeutic landscape for NRs has expanded with the approval of drugs like PPARγ agonists (pioglitazone, rosiglitazone) for diabetes, FXR agonists (obeticholic acid) for liver diseases, and selective TR agonists (resmetirom) for Metabolic dysfunction-Associated Steatohepatitis (MASH). However, challenges such as tissue-specific activation, drug resistance in chronic diseases, and potential carcinogenic risks continue to limit the full clinical efficacy of NR-targeted therapies. Emerging therapeutic strategies, including selective nuclear receptor modulators (SNRMs), dual and pan-NR agonists, and gene therapy approaches, aim to enhance receptor specificity while minimizing adverse effects. Furthermore, advances in artificial intelligence-driven drug discovery, CRISPR-based gene therapy, and microbiome-targeted interventions hold significant promise for refining the therapeutic efficacy and safety of NR-based treatments. A deeper understanding of NR crosstalk with metabolic, inflammatory, and oncogenic pathways will be crucial for developing next-generation therapies to overcome resistance mechanisms and improve clinical outcomes. These advancements, combined with precision medicine approaches, are poised to revolutionize NR-targeted therapies, offering more precise, effective, and safer treatments for a range of metabolic, inflammatory, and oncological diseases.
核受体（NRs）是一类配体激活的转录因子超家族，可响应代谢、激素和环境信号调节基因表达。这些受体在代谢稳态、炎症、免疫功能和疾病发病机制中发挥关键作用，使其成为关键的治疗靶点。本综述探讨了PPARs、FXR、LXR和甲状腺激素受体（THRs）等核受体在调节脂质和葡萄糖代谢、能量消耗、心血管健康和神经退行性变中的机制作用。随着PPARγ激动剂（吡格列酮、罗格列酮）用于治疗糖尿病、FXR激动剂（奥贝胆酸）用于治疗肝病以及选择性TR激动剂（瑞美替隆）用于治疗代谢功能障碍相关脂肪性肝炎（MASH）等药物的获批，核受体的治疗前景得到了拓展。然而，组织特异性激活、慢性病中的耐药性以及潜在致癌风险等挑战仍然限制了以核受体为靶点的治疗方法的全面临床疗效。新兴的治疗策略，包括选择性核受体调节剂（SNRMs）、双功能和泛核受体激动剂以及基因治疗方法，旨在提高受体特异性，同时将不良反应降至最低。此外，人工智能驱动的药物发现、基于CRISPR的基因治疗以及针对微生物群的干预措施的进展，为提高基于核受体的治疗的疗效和安全性带来了巨大希望。深入了解核受体与代谢、炎症和致癌途径的相互作用，对于开发新一代疗法以克服耐药机制并改善临床结果至关重要。这些进展与精准医学方法相结合，有望彻底改变以核受体为靶点的治疗方法，为一系列代谢、炎症和肿瘤疾病提供更精确、有效和安全的治疗。
