AbstractBackground and AimsSteatotic liver disease (SLD) is generally considered to represent a hepatic manifestation of metabolic syndrome and includes a disease spectrum comprising isolated steatosis, metabolic dysfunction‐associated steatohepatitis, liver fibrosis and ultimately cirrhosis. A better understanding of the detailed underlying pathogenic mechanisms of this transition is crucial for the design of new and efficient therapeutic interventions. Thymocyte differentiation antigen (Thy‐1, also known as CD90) expression on fibroblasts controls central functions relevant to fibrogenesis, including proliferation, apoptosis, cytokine responsiveness, and myofibroblast differentiation.MethodsThe impact of Thy‐1 on the development of SLD and progression to fibrosis was investigated in high‐fat diet (HFD)‐induced SLD wild‐type and Thy‐1‐deficient mice. In addition, the serum soluble Thy‐1 (sThy‐1) concentration was analysed in patients with metabolic dysfunction‐associated SLD stratified according to steatosis, inflammation, or liver fibrosis using noninvasive markers.ResultsWe demonstrated that Thy‐1 attenuates the development of fatty liver and the expression of profibrogenic genes in the livers of HFD‐induced SLD mice. Mechanistically, Thy‐1 directly inhibits the profibrotic activation of nonparenchymal liver cells. In addition, Thy‐1 prevents palmitic acid‐mediated amplification of the inflammatory response of myeloid cells, which might indirectly contribute to the pronounced development of liver fibrosis in Thy‐1‐deficient mice. Serum analysis of patients with metabolically associated steatotic liver disease syndrome revealed that sThy‐1 expression is correlated with liver fibrosis status, as assessed by liver stiffness, the Fib4 score, and the NAFLD fibrosis score.ConclusionOur data strongly suggest that Thy‐1 may function as a fibrosis‐protective factor in mouse and human SLD.