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Dysregulated lipid metabolism is crucial in the pathogenesis of NASH. However, its regulatory mechanisms remain intricate and poorly elucidated. Hepatic stellate cells (HSCs) have been reported to contribute to hepatocellular lipid metabolism dysregulation and aggravate NASH progression. However, the potential mechanisms remain unclear. Here, we demonstrate that hydrogen peroxide-inducible clone 5 (Hic-5), which is highly expressed in HSCs within the liver, is elevated in NASH patients and mouse models. Hic-5 deficiency alleviates hepatic steatosis, and liver metabolomics revealed reduced fatty acid levels. Meanwhile, RNA-sequencing revealed that Hic-5 deficiency increases AMPK phosphorylation. Additionally, HSC-specific overexpression of Hic-5 exacerbates NASH severity. Co-culture experiments indicated that Hic-5 increases hepatocellular fatty acid synthesis. Cellular transcriptomic analysis and validation revealed that prostaglandin E2 (PGE2), secreted by HSCs, mediates hepatocellular fatty acid synthesis. Mechanistically, the N-terminal domain of Hic-5 binds c-Src, leading to phosphorylation of PTEN, which is bound to the C-terminal domain. This event subsequently induces phosphorylation and nuclear translocation of the transcription factor SP1, ultimately increasing PGE2 secretion. Finally, Hic-5 promotes hepatocellular fatty acid synthesis by activating the PGE2-EP4 axis. Pharmacological inhibition of EP4 in HSC-specific Hic-5 overexpression mice fed with HFD diet (HFD) significantly attenuated NASH progression. These findings increase our understanding of molecular mechanisms linking hepatic lipid metabolism dysregulation and may offer therapeutic potential for treating NASH.<\/jats:p>","DOI":"10.1186\/s43556-026-00409-4","type":"journal-article","created":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T07:50:20Z","timestamp":1770623420000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Hic-5 promotes the progression of nonalcoholic steatohepatitis by regulating hepatocellular fatty acid metabolism through the PTEN\/PGE2\/EP4 axis"],"prefix":"10.1186","volume":"7","author":[{"given":"Zhiwei","family":"Huang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boyuan","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shenglu","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiatong","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingyu","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9672-8079","authenticated-orcid":false,"given":"Wenguang","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,9]]},"reference":[{"key":"409_CR1","doi-asserted-by":"publisher","unstructured":"Adorini L, Trauner M. 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Studies of these specimens were conducted in accordance with the 1975 Declaration of Helsinki. All the animal experiments we performed followed the Animal Experimentation Ethics Committee of Southwest Medical University.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"We have obtained consents to publish this paper from all the participants of this study.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"10"}}