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Interferon regulatory factor 7 (IRF7) is a central mediator of type I interferon-dependent immune responses, yet the precise mechanisms by which macrophage-expressed IRF7 shapes inflammatory and metabolic events during MASH pathogenesis remain incompletely defined. This study aimed to dissect the functional role of IRF7 in MASH development. We assessed IRF7 expression in human and mouse liver specimens, and utilized myeloid-specific\n                    <jats:italic>Irf7<\/jats:italic>\n                    -deficient mice fed with high-fat high-cholesterol diet (HFHCD) or methionine-choline-deficient diet (MCD) to recapitulate MASH pathology. IRF7 was significantly elevated in MASH-affected livers, and myeloid-specific\n                    <jats:italic>Irf7<\/jats:italic>\n                    deletion markedly mitigated MASH progression. Mechanistically, loss of IRF7 blunted IFN-\u03b1 and IFN-\u03b2 production, suppressing macrophage-derived type I interferon-dependent immune cascades. IRF7 directly bound to the promoters of pro-inflammatory\n                    <jats:italic>Tnfa<\/jats:italic>\n                    and\n                    <jats:italic>Il1b<\/jats:italic>\n                    to boost their transcription, and interacted with SMAD3 to activate\n                    <jats:italic>Tgfb1<\/jats:italic>\n                    transcription. The E3 ubiquitin ligase HUWE1 mediated IRF7 monoubiquitination to enhance its nuclear translocation, driving transcription of pro-inflammatory and pro-fibrotic genes. This molecular cascade aggravated hepatic steatosis and triggered hepatic stellate cell (HSC) activation, accelerating MASH deterioration. Pharmacological IRF7 inhibition effectively counteracted these pathological alterations. Collectively, myeloid IRF7 fuels MASH progression by amplifying macrophage-mediated liver inflammation, suggesting IRF7 as a promising therapeutic target against MASH.\n                  <\/jats:p>","DOI":"10.1186\/s43556-026-00601-6","type":"journal-article","created":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T07:47:49Z","timestamp":1792396069000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Macrophage interferon regulatory factor 7 aggravates the progression of metabolic dysfunction-associated steatohepatitis"],"prefix":"10.1186","volume":"7","author":[{"given":"Xuhao","family":"Ni","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingfa","family":"Bu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bozhou","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingxiang","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,19]]},"reference":[{"issue":"10","key":"601_CR1","doi-asserted-by":"publisher","first-page":"2537","DOI":"10.1016\/j.cell.2021.04.015","volume":"184","author":"R Loomba","year":"2021","unstructured":"Loomba R, Friedman SL, Shulman GI. 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