{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T08:26:04Z","timestamp":1787214364108,"version":"build-2736575974"},"reference-count":56,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"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. Pharmacol."],"abstract":"<jats:p>Renal fibrosis is a common pathological process underlying the progression of various kidney diseases to end-stage renal disease. It is characterized by the activation of renal interstitial fibroblasts and excessive deposition of the extracellular matrix (ECM). Continued progression can lead to irreversible loss of renal function, but effective targeted therapies are currently lacking. In recent years, nuclear receptor 4A1 (NR4A1) has been shown to bidirectionally regulate renal fibrosis. Nuclear NR4A1 exerts anti-fibrotic effects by inhibiting pathways such as TGF-\u03b2\/Smad and NF-\u03baB. However, upon pathological stimulation, NR4A1 translocates to the cytoplasm and mitochondria, where it promotes fibrosis by activating the NLRP3 inflammasome and p38 MAPK signaling and inducing mitochondrial damage. Thus, the functional outcome of NR4A1 is highly dependent on its subcellular localization. This review focuses on the dual anti-fibrotic and pro-fibrotic mechanisms of NR4A1 in renal fibrosis. Based on the regulation of its subcellular localization shifts, we explore targeted intervention strategies aimed at precisely stabilizing its nuclear protective function while blocking pathological nuclear export, thereby providing new directions for treating renal fibrosis.<\/jats:p>","DOI":"10.3389\/fphar.2026.1883285","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T08:16:10Z","timestamp":1787213770000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The subcellular localization-dependent dual role of NR4A1 in renal fibrosis: mechanisms and therapeutic perspectives"],"prefix":"10.3389","volume":"17","author":[{"given":"Xu","family":"Li","sequence":"first","affiliation":[{"name":"The Nephrology Department of Shanxi Provincial People\u2019s Hospital, Shanxi Medical University","place":["Taiyuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufeng","family":"Qiao","sequence":"additional","affiliation":[{"name":"The Nephrology Department of Shanxi Provincial People\u2019s Hospital","place":["Taiyuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1186\/s11658-020-00241-w","article-title":"The nuclear receptor 4A family members: mediators in human disease and autophagy","volume":"25","author":"Chen","year":"2020","journal-title":"Cell Mol. 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