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Hepatic stellate cells (HSCs) are the principal precursor cells that transdifferentiate into myofibroblast\u2010like cells, which produce a large amount of extracellular matrix that promotes repair but can also lead to fibrosis if the injury becomes chronic. The matricellular protein cellular communication network factor 1 (CCN1) acts as a bridging molecule by binding phosphatidylserine in apoptotic cells and integrin \u03b1<jats:sub>v<\/jats:sub>\u03b2<jats:sub>3<\/jats:sub> in phagocytes, thereby triggering efferocytosis or phagocytic clearance of the apoptotic cells. Here, we show that CCN1 induces liver macrophage efferocytosis of apoptotic neutrophils in carbon tetrachloride (CCl<jats:sub>4<\/jats:sub>)\u2010induced liver injury, leading to the production of activated transforming growth factor (TGF)\u2010\u03b21, which in turn induces HSC transdifferentiation into myofibroblast\u2010like cells that promote fibrosis development. Consequently, knock\u2010in mice expressing a single amino acid substitution in CCN1 rendering it unable to bind \u03b1<jats:sub>v<\/jats:sub>\u03b2<jats:sub>3<\/jats:sub> or induce efferocytosis are impaired in neutrophil clearance, production of activated TGF\u2010\u03b21, and HSC transdifferentiation, resulting in greatly diminished liver fibrosis following exposure to CCl<jats:sub>4<\/jats:sub>. <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic> These results reveal the crucial role of CCN1 in stimulating liver macrophage clearance of apoptotic neutrophils, a process that drives HSC transdifferentiation into myofibroblastic cells and underlies fibrogenesis in chronic liver injury.<\/jats:p>","DOI":"10.1002\/hep4.2057","type":"journal-article","created":{"date-parts":[[2022,8,5]],"date-time":"2022-08-05T12:59:20Z","timestamp":1659704360000},"page":"2798-2811","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":27,"title":["Cellular communication network factor 1\u2010stimulated liver macrophage efferocytosis drives hepatic stellate cell activation and liver fibrosis"],"prefix":"10.1097","volume":"6","author":[{"given":"Ki\u2010Hyun","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics,University of Illinois at Chicago, College of Medicine,Chicago,Illinois,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naiyuan","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics,University of Illinois at Chicago, College of 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