Abstract

There has been extensive interest in metabolic dysfunction-associated steatotic liver disease (MASLD) and its more advanced stage, metabolic dysfunction-associated steatohepatitis (MASH). Although several studies have highlighted the importance of hepatocyte Notch signaling in MASH-related liver fibrosis, the role of macrophage Notch signaling in MASH-related fibrosis has been less explored. This study found that Notch1 signaling in hepatic macrophages was significantly activated in a high-fat diet (HFD)-induced mouse model of MASH. Depletion of myeloid Notch1 led to a significant reduction in disease progression in this HFD-induced MASH model, as evidenced by reduced hepatic inflammation, steatosis, and fibrosis in HFD-fed, myeloid-specific Notch1 knockout mice. Intriguingly, disruption of Notch1 suppressed the expression of Gli1, a key transcription factor in the Hedgehog signaling pathway, and promoted M2-like macrophage polarization in the injured liver. Furthermore, the Notch1 deletion-mediated effects—namely, M2 macrophage polarization and the reduction in hepatic steatosis and fibrosis—were reversed by treatment with the Hedgehog agonist SAG in HFD-fed mice. In vitro experiments further demonstrated that Notch1 deletion promoted a shift in macrophage polarization toward the M2 phenotype by inhibiting Gli1 expression. Collectively, these findings identify the Notch1–Gli1 axis as a novel regulator of macrophage polarization, hepatic inflammation, steatosis, and fibrosis in MASH.