Inhibition of STAT1 alleviates MAIT cell dysfunction and attenuates disease progression in metabolic dysfunction-associated steatotic liver disease

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common chronic liver disease with limited effective therapeutic options and an incompletely understood pathogenesis. Dysregulation of immune cells plays a crucial role in driving MASLD progression. Thus, elucidating the immunoregulatory mechanisms underlying MASLD is essential for the development of novel therapeutic strategies. In this study, single-cell RNA sequencing was performed to systematically analyze the immune composition of peripheral blood mononuclear cells (PBMCs) from MASLD patients and healthy controls. Mucosal-associated invariant T (MAIT) cells were found to be significantly increased in MASLD and exhibited high expression of inflammation-related genes. Flow cytometry, Immunofluorescence, animal models, and in vitro experiments indicated that STAT1 plays a key role in regulating MAIT cell differentiation and proinflammatory function. STAT1 was markedly upregulated in MAIT cells from MASLD patients, and STAT1 inhibition significantly suppressed MAIT cell maturation and inflammatory cytokine secretion, thereby ameliorating MASLD progression. In summary, our study demonstrates that STAT1-mediated MAIT cell dysfunction is critically involved in MASLD progression, and identifies STAT1 as a promising immunotherapeutic target, providing a theoretical basis for future clinical interventions.