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Ligustilide (LIG) has been reported to possess anti\u2011fibrotic activity; however, its protective effects and underlying molecular mechanisms in renal fibrosis remain incompletely understood. This study examined the effects of LIG and explored its underlying mechanisms in a unilateral ureteral obstruction (UUO) mouse model and TGF\u2011\u03b21\u2010stimulated mouse renal tubular epithelial cell (TCMK1) cells. In\u00a0vivo, LIG (20 and 40 mg\u00b7kg\u207b\n                    <jats:sup>1<\/jats:sup>\n                    ) significantly alleviated renal pathological injury in UUO mice, reduced tubular dilatation, and downregulated the expression of the renal injury marker KIM\u20111 as well as fibrosis\u2011related proteins, including fibronectin, collagen I, and \u03b1\u2011SMA. In\u00a0vitro, LIG dose\u2011dependently inhibited TGF\u2011\u03b21\u2011induced fibrotic responses in TCMK1 cells. Target screening using drug affinity responsive target stability (DARTS)\u2011coupled liquid chromatography\u2013mass spectrometry (LC\/MS) identified Fblim1 as a putative target of LIG. Cellular thermal shift assay (CETSA) and DARTS assays further confirmed that LIG directly binds to Fblim1, enhancing its thermal stability and protease resistance. Both in\u00a0vivo and in\u00a0vitro, LIG treatment reduced the mRNA and protein levels of Fblim1 and phosphorylated Smad3 (p\u2011Smad3). Notably, LIG suppressed the nuclear accumulation of Fblim1 and p\u2011Smad3, thereby attenuating TGF\u2011\u03b21\/Smad3\u2011mediated profibrotic signaling. The results reveal that ligustilide exerts its anti\u2011renal fibrotic effects by targeting Fblim1 and regulating the TGF\u2011\u03b21\/Smad3 signaling pathway, particularly its nuclear translocation process.\n                  <\/jats:p>","DOI":"10.1002\/ptr.70305","type":"journal-article","created":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T00:30:08Z","timestamp":1773707408000},"page":"3063-3076","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Ligustilide Alleviates Renal Fibrosis Through Fblim1\u2010Dependent Inhibition of the\n                    <scp>TGF<\/scp>\n                    \u2010\u03b21\/Smad3 Signaling Pathway"],"prefix":"10.1002","volume":"40","author":[{"given":"Quwu","family":"Mushuo","sequence":"first","affiliation":[{"name":"Institute of Integrated Chinese and Western Medicine, Southwest Medical University  Luzhou 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