{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T02:23:33Z","timestamp":1789439013935,"version":"build-2803163510"},"reference-count":113,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T00:00:00Z","timestamp":1768953600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>Chronic low-grade inflammation (metaflammation) constitutes a shared pathological nexus in obesity, type 2 diabetes mellitus (T2DM), and non-alcoholic fatty liver disease (NAFLD). While current therapies primarily alleviate metabolic symptoms, they often neglect underlying immune dysregulation orchestrated by nuclear receptors (NRs). This review proposes immune-centric pharmacology, a paradigm directly targeting immunocytes (e.g., macrophages, T cells) through spatiotemporal modulation of NR-mediated immunometabolic crosstalk (e.g., PPAR\u03b3\/\u03b4, FXR, LXRs) to disrupt inflammation-perpetuating microenvironments. We emphasized NRs as main regulatory factors of immunophenotypic reprogramming, spanning the interactions of fat, liver, and intestinal immunity, and comprehensively summarized the multicellular structure of \u201cinflamed nexus.\u201d We gradually expand our discussion from the following three aspects: immune reprogramming targeting nr by novel biological agents (for example, TREM2 agonists activating PPAR\u03b3); advanced transmission systems enable tissue-specific NR regulation.; and the immunomodulatory mechanism of metabolic drugs utilizing the NR-immune axis. Current findings indicate that focused immunomodulation achieves via NR-guided immune-centric pharmacology represents a transformative framework for next-generation metabolic disease management, bridging pharmacological innovation with therapeutic translation.<\/jats:p>","DOI":"10.3389\/fcell.2025.1706384","type":"journal-article","created":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T06:43:37Z","timestamp":1768977817000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Nuclear receptor-driven immunometabolic crosstalk: immune-centric pharmacology targeting the inflamed nexus"],"prefix":"10.3389","volume":"13","author":[{"given":"Yang","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Endocrinology, Guang\u2019anmen Hospital, China Academy of Chinese Medical Sciences","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenzhen","family":"Pei","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Guang\u2019anmen Hospital, China Academy of Chinese Medical Sciences","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhige","family":"Wen","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Guang\u2019anmen Hospital, China Academy of Chinese Medical Sciences","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yupeng","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Guang\u2019anmen Hospital, China Academy of Chinese Medical Sciences","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoshuo","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Guang\u2019anmen Hospital, China Academy of Chinese Medical Sciences","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weili","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Guang\u2019anmen Hospital, China Academy of Chinese Medical Sciences","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Guang\u2019anmen Hospital, China Academy of Chinese Medical Sciences","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingbo","family":"Liu","sequence":"additional","affiliation":[{"name":"Hohhot Mongolian and Traditional Chinese Medicine Hospital","place":["Hohhot, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Ni","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Guang\u2019anmen Hospital, China Academy of Chinese Medical Sciences","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1021\/acs.jmedchem.2c01266","article-title":"Rational design of a new RXR agonist scaffold enabling single-subtype preference for RXR\u03b1, RXR\u03b2, and RXR\u03b3","volume":"66","author":"Adouvi","year":"2023","journal-title":"J. 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