{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T13:16:42Z","timestamp":1785417402269,"version":"3.56.0"},"reference-count":32,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T00:00:00Z","timestamp":1777507200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82073317"],"award-info":[{"award-number":["82073317"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82573222"],"award-info":[{"award-number":["82573222"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"award":["82073317"],"award-info":[{"award-number":["82073317"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["82573222"],"award-info":[{"award-number":["82573222"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100018598","name":"Guangdong Esophageal Cancer Research Institute","doi-asserted-by":"crossref","award":["Q-202208"],"award-info":[{"award-number":["Q-202208"]}],"id":[{"id":"10.13039\/501100018598","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Chronic liver injury is characterized by sustained activation of transforming growth factor-\u03b2 (TGF-\u03b2) signaling within the fibrotic microenvironment, yet the contribution of TGF-\u03b2-associated metabolic remodeling to hepatic stellate cell (HSC) activation remains incompletely understood. Here, we investigated whether TGF-\u03b2 signaling is associated with lipid metabolic remodeling in HSCs and whether pirfenidone (PFD) interferes with this process. We found that TGF-\u03b21 was spatially associated with lipid accumulation in fibrotic liver tissue and that TGF-\u03b21\/2 promoted HSC proliferation. In vitro, TGF-\u03b21\/2 coordinately upregulated sterol regulatory element-binding protein 1 (SREBP1) and fatty acid synthase (FASN), accompanied by increased intracellular lipid accumulation and enhanced oleic acid (OA)-associated lipid responses. Low-dose OA further activated AKT\/ERK\/p70 S6K signaling in HSCs, whereas PFD attenuated these signaling events. In parallel, PFD suppressed TGF-\u03b2-associated lipid accumulation in vitro, reduced SREBP1\/FASN expression in activated HSC-rich regions in vivo, and alleviated CCl4-induced liver fibrosis. Together, these findings support a model in which TGF-\u03b2-associated lipogenic remodeling contributes to HSC activation and suggest that interference with this metabolic state may represent one component of the antifibrotic action of pirfenidone.<\/jats:p>","DOI":"10.3390\/ijms27094061","type":"journal-article","created":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T06:50:01Z","timestamp":1777618201000},"page":"4061","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Pirfenidone Suppresses Liver Fibrosis Through Inhibition of TGF-\u03b2-Associated Lipid Metabolic Remodeling in Hepatic Stellate Cells"],"prefix":"10.3390","volume":"27","author":[{"given":"Yuelu","family":"Lan","sequence":"first","affiliation":[{"name":"State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sijia","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuangli","family":"Zhu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Can","family":"Pan","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Fu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3519-3100","authenticated-orcid":false,"given":"Xueping","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liwu","family":"Fu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1001\/jama.2025.19615","article-title":"Metabolic Dysfunction\u2013Associated Steatotic Liver Disease in Adults: A Review","volume":"335","author":"Tilg","year":"2026","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"S5","DOI":"10.3350\/cmh.2022.0424","article-title":"Non-Alcoholic Fatty Liver Disease: Definition and Subtypes","volume":"29","author":"Han","year":"2023","journal-title":"Clin. 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