{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T19:29:52Z","timestamp":1788809392396,"version":"build-2803163510"},"reference-count":146,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T00:00:00Z","timestamp":1770595200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of Education, University, and Research (MIUR), Progetti di Rilevante Interesse Nazionale","award":["2022P5LPHS"],"award-info":[{"award-number":["2022P5LPHS"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Metabolic disorders, including metabolic dysfunction-associated fatty liver disease (MAFLD), obesity, and dyslipidemia, impose a substantial and escalating global health burden, highlighting an urgent need for effective pharmacotherapies. Selective modulation of nuclear receptors (NRs) has emerged as a promising strategy to restore metabolic homeostasis. This review focuses on three therapeutically pivotal yet under-explored NRs: thyroid hormone receptor \u03b2 (TR\u03b2), estrogen-related receptor \u03b1 (ERR\u03b1), and liver X receptor (LXR\u03b1\/\u03b2). We critically examine recent advances in the development of small-molecule modulators for these targets and discuss their translational potential. TR\u03b2 agonists, including resmetirom (MGL-3196) and VK2809, have demonstrated compelling efficacy in clinical trials for metabolic dysfunction-associated steatohepatitis (MASH), significantly reducing hepatic steatosis and fibrosis. Next-generation hepatoselective modulators such as TG68 enhance tissue specificity and potency. ERR\u03b1, a master regulator of mitochondrial biogenesis and energy metabolism, is targeted by inverse agonists (compound 29, GSK5182) and agonists (JND003, SLU-PP-915), which show promise in ameliorating insulin resistance and promoting lipid oxidation in preclinical obesity models. LXRs, central players in cholesterol homeostasis, are the focus of innovative drug design aimed at harnessing atheroprotective benefits via LXR\u03b2-selective or partial agonists, thereby circumventing adverse effects on triglyceride synthesis. Collectively, the ongoing development of TR\u03b2, ERR\u03b1, and LXR modulators exemplifies a new frontier in precision medicine, offering powerful approaches to reprogram dysregulated metabolic pathways with substantial promise for treating metabolic diseases.<\/jats:p>","DOI":"10.3390\/biom16020272","type":"journal-article","created":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T09:41:02Z","timestamp":1770630062000},"page":"272","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Nuclear\u00a0Receptor-Targeted Therapies: Reprogramming Metabolism with TR\u03b2, ERR\u03b1, and LXR Modulators"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6950-4467","authenticated-orcid":false,"given":"Carmen","family":"Di Giovanni","sequence":"first","affiliation":[{"name":"\u201cDrug Discovery\u201d Laboratory, Department of Pharmacy, University of Naples Federico II, I-80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2181-8026","authenticated-orcid":false,"given":"Antonio","family":"Lavecchia","sequence":"additional","affiliation":[{"name":"\u201cDrug Discovery\u201d Laboratory, Department of Pharmacy, University of Naples Federico II, I-80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,9]]},"reference":[{"key":"ref_1","unstructured":"GBD 2023 Disease and Injury and Risk Factor Collaborators (2025). 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