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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 PPAR\u03b3 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. 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