BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a large group of metabolic diseases that are hazardous to human health. Endothelial-to-mesenchymal transition (EndMT) mediated myofibroblast activation is an important factor that aggravates the development of liver fibrosis during MASH. However, the limited understanding of the underlying molecular mechanisms that drive EndMT in MASH has hindered the development of molecularly targeted therapies specifically targeting this pathological process. METHODS: We employed wild-type and ifn-γ-deficient mice, MASH models were induced repeated CCl RESULTS: The results showed that IFN-γ is revealed as a key regulator of EndMT during MASH, as evidenced by the significantly lower levels of EndMT and reduced pathological damage in the livers of ifn-γ knockout mice. Furthermore, our research has led to the development of Scutellarin@BSA therapy, which targets and mitigates IFN-γ-driven EndMT, which showed excellent therapeutic effects on EndMT and liver fibrosis in vivo and in vitro during MASH. Mechanistically, IFN-γ can directly bind to the JAK protein and activate downstream STAT1 transcription factors, exerting transcriptional activity and further driving the expression of EndMT-associated proteins. Notably, Scutellarin@BSA treatment effectively diminishes the hallmarks of liver fibrosis by modulating the canonical JAK/STAT1 signaling pathway. CONCLUSIONS: IFN-γ was identified as a key regulator of EndMT, and Scutellarin@BSA, as an emerging treatment, has been found to effectively inhibit EndMT by directly targeting the regulatory influence of the IFN-γ signaling. This result demonstrates significant therapeutic efficacy in alleviating hepatic fibrosis during MASH, highlighting its great potential as an innovative liver fibrosis treatment.