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TIM3 is a promising protector in MCD-induced steatohepatitis in acute liver injury. However, we recently find TIM3 as a driver of fibrosis in MCD\/HFD-induced chronic liver injury. This study aims to explore how macrophage TIM3 drivers NAFLD-associated chronic liver injury as well as identify a subtype of fibrotic patients suitable for anti-TIM3 immunotherapy. Here, we found that TIM3 was highly expressed in liver macrophages in a long-term MCD- or HFD-fed mice with fibrotic NASH. Elevated \u03b2-TrCP in macrophages promoted TIM3 polyubiquitination and membrane translocation. The ubiquitinated TIM3 then bound with PI3K and followed by inhibition of mTOR and activation of macrophage M2 polarization and TGF-\u03b2 release, leading to HSC activation and liver fibrosis. Furthermore, elevated TIM3 was attributed to the transcriptional TBP upregulation and miR-4524a-5p downregulation. Targeting of TIM3 significantly attenuated liver fibrosis in mice. In clinical NASH patients, elevated macrophage TIM3 is positively correlated with TBP expression and negatively associated with miR-4524a-5p. Decreased miR-4524a-5p in plasma was a biomarker for the NASH fibrosis patients suitable for anti-TIM3 therapy. In conclusion, this study reveals that miR-4524a-5p\/TBP promotes \u03b2-TrCP\/TIM3 complex activation in macrophages and aggravates chronic NASH fibrosis, providing miR-4524a-5p as an effective blood biomarker for a subtype of chronic NASH patients with fibrosis suitable for anti-TIM3 treatment.<\/jats:p>","DOI":"10.1038\/s41419-025-07574-4","type":"journal-article","created":{"date-parts":[[2025,4,19]],"date-time":"2025-04-19T00:36:51Z","timestamp":1745023011000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Macrophage miR-4524a-5p\/TBP promotes \u03b2-TrCP -TIM3 complex activation and TGF\u03b2 release and aggravates NAFLD-associated fibrosis"],"prefix":"10.1038","volume":"16","author":[{"given":"Chunming","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingxing","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haojun","family":"Xiong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongqiang","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhu","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaotong","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Min","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9707-3390","authenticated-orcid":false,"given":"Zhiyu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5577-1481","authenticated-orcid":false,"given":"Jianping","family":"Gong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4362-6612","authenticated-orcid":false,"given":"Chuan-Ming","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,19]]},"reference":[{"key":"7574_CR1","doi-asserted-by":"publisher","first-page":"1999","DOI":"10.1053\/j.gastro.2019.11.312","volume":"158","author":"M Eslam","year":"2020","unstructured":"Eslam M, Sanyal AJ, George J. 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