{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,24]],"date-time":"2025-12-24T10:10:41Z","timestamp":1766571041593,"version":"3.48.0"},"reference-count":28,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,21]],"date-time":"2025-12-21T00:00:00Z","timestamp":1766275200000},"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":"publisher","award":["32560025"],"award-info":[{"award-number":["32560025"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82160135"],"award-info":[{"award-number":["82160135"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82360146"],"award-info":[{"award-number":["82360146"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Hainan Provincial Natural Science Foundation of China","award":["825MS069"],"award-info":[{"award-number":["825MS069"]}]},{"name":"Excellent Talent Team Project in Hainan Province","award":["HNYT20250004"],"award-info":[{"award-number":["HNYT20250004"]}]},{"name":"Hainan key research and development projects","award":["ZDYF2025SHFZ041"],"award-info":[{"award-number":["ZDYF2025SHFZ041"]}]},{"name":"Academic Enhancement Program of Hainan Medical University","award":["XSTS2025102"],"award-info":[{"award-number":["XSTS2025102"]}]},{"name":"Hainan Province Clinical Medical Center"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: To explore the protective effects of 7-Ketolithocholic acid (7-KLCA) against renal fibrosis and its mechanism, focusing on its interaction with farnesoid X receptor (FXR). Methods: In vitro, TGF-\u03b2-induced fibrosis in HK-2\/NRK-49F cells and LPS-induced inflammation in HK-2 cells were detected by CCK-8, Western blot, and qPCR. In vivo, unilateral ureteral obstruction (UUO) and adenine (Ade)-induced mouse models were treated with a low\/high-dose 7-KLCA or losartan. Renal injury was evaluated via H&amp;E\/Masson staining, serum creatinine (SCR), and blood urea nitrogen (BUN) levels. The 7-KLCA-FXR interaction was verified by molecular docking, CETSA, and DARTS. FXR downstream genes and related proteins were measured by WB and qPCR. Results: 7-KLCA inhibited the expression of fibrotic proteins (fibronectin, collagen-I) and reduced the LPS-induced release of inflammatory factors (IL-1\u03b2, IL-6). In mice, it alleviated renal swelling, collagen deposition, and tubular damage, while lowering serum SCR and BUN levels. Mechanistically, 7-KLCA stably bound to the FXR ligand-binding domain, enhanced its thermal stability and degradation resistance. It upregulated FXR and its downstream genes SHP and FGF15, thereby inhibiting the activation of TGF-\u03b2\/Smad and Wnt\/\u03b2-catenin pathways. Conclusions: This is the first study to clarify the molecular mechanism through which 7-KLCA targets FXR and dually suppresses the key pro-fibrotic pathways TGF-\u03b2\/Smad and Wnt\/\u03b2-catenin, thereby exerting anti-renal fibrosis effects.<\/jats:p>","DOI":"10.3390\/ph19010015","type":"journal-article","created":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T07:01:33Z","timestamp":1766386893000},"page":"15","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["7-Ketolithocholic Acid Exerts Anti-Renal Fibrotic Effects Through FXR-Mediated Inhibition of TGF-\u03b2\/Smad and Wnt\/\u03b2-Catenin Pathways"],"prefix":"10.3390","volume":"19","author":[{"given":"Qicheng","family":"Guo","sequence":"first","affiliation":[{"name":"Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lianye","family":"Peng","sequence":"additional","affiliation":[{"name":"Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingyi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junming","family":"Hu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0323-5345","authenticated-orcid":false,"given":"Yinyin","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines, Department of TCMs Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiali","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Hainan Affiliated Hospital of Hainan Medical University (Hainan General Hospital), Haikou 470100, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhihao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"111200","DOI":"10.1016\/j.celrep.2022.111200","article-title":"APOE4 drives inflammation in human astrocytes via TAGLN3 repression and NF-\u03baB activation","volume":"40","author":"Arnaud","year":"2022","journal-title":"Cell Rep."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"194","DOI":"10.7150\/ijbs.39024","article-title":"Ruxolitinib Alleviates Renal Interstitial Fibrosis in UUO Mice","volume":"16","author":"Bai","year":"2020","journal-title":"Int. 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