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Emerging evidence has established a critical link between macrophage extracellular traps (METs) and LFib; however, the precise triggers of METs formation and their mechanistic contributions to fibrosis remain poorly understood. Substantial evidence indicates that interleukin-25 (IL-25) potently regulates macrophage metabolism and LFib progression. A carbon tetrachloride (CCl\u2084)-induced mouse model of liver fibrosis spanning distinct stages (2 to 8\u00a0weeks) was established. In vitro studies utilized co-culture systems and conditioned medium treatment to assess METs-mediated activation of hepatic stellate cells (HSCs). To elucidate the specific role of IL-25, hepatocyte-specific IL-25 conditional knockout (IL-25CKO) mice were generated using CRISPR\/Cas9 technology and subjected to the LFib model. Mechanistic investigations involved stimulating RAW 264.7 macrophages with rmIl-25 and specific inhibitors. Techniques such as scanning\/transmission electron microscopy, immunofluorescence, Western blot and ELISA were employed to analyze MET formation, ROS production, lysosomal activation, mitophagy, and related signaling pathways. Fibrotic livers exhibited strong early co-localization of IL-25 with hepatocytes, which preceded METs formation. This demonstrates that early production of IL-25 by hepatocytes acts as a triggering factor for METs formation. In vitro co-culture systems revealed METs-mediated activation of HSCs, while mechanistic studies showed that IL-25 promotes IL-17RB receptor activation, triggering downstream reactive oxygen species (ROS) bursts, lysosomal activation, and METs formation. This work identifies a pathogenic hepatocyte\u2013macrophage\u2013HSC axis and supports IL-25 early blockade as a promising clinical strategy for LFib.<\/jats:p>","DOI":"10.1007\/s10753-026-02506-6","type":"journal-article","created":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T16:17:30Z","timestamp":1775060250000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Hepatocyte-Derived IL-25 Promotes Macrophage Extracellular Trap Formation and Drives Liver Fibrosis Progression"],"prefix":"10.1007","volume":"49","author":[{"given":"Cheng-Jiang","family":"Cao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang-Lin","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"He-Hang","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Jing","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miao-Miao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Mei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen-Long","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,1]]},"reference":[{"key":"2506_CR1","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1172\/JCI24282","volume":"115","author":"R Bataller","year":"2005","unstructured":"Bataller, R., and D.A. 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All animal experiments were performed in accordance with the Institutional Animal Experimentation Ethics Committee of Anhui Medical University (LLSC20251049).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical Approval and Participation Consent"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"Clinical trial number: not applicable.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Clinical Trial"}}],"article-number":"139"}}