Depletion of NAT10 in T cells attenuates metabolic dysfunction-associated steatohepatitis in mice

Metabolic dysfunction-associated steatohepatitis (MASH) is a leading cause of chronic liver disease, yet its pathogenesis remains incompletely understood. Immune dysregulation, particularly intrahepatic T-cell responses, is implicated in disease progression; however, the specific roles of T-cell subsets and their regulatory mechanisms are not fully defined.

We performed single-cell RNA sequencing (scRNA-seq) on human liver tissues from patients with varying severities of metabolic dysfunction-associated steatotic liver disease (MASLD). To establish causality, we generated T cell-specific NAT10 knockout mice. The molecular mechanism was elucidated using acetylated RNA immunoprecipitation sequencing (acRIP-seq) and mRNA stability assays.

scRNA-seq revealed a marked increase in NAT10 expression in intrahepatic effector CD8+ T cells from patients with severe MASLD. In mice, T cell-specific deletion of NAT10 significantly attenuated MASH progression, reducing hepatocyte injury, fibrosis, and intrahepatic CD8+ T cell accumulation. NAT10 deficiency suppressed CD8+ T cell cytotoxicity, evidenced by decreased production of IFN-γ, TNF-α, and GZMB. Mechanistically, NAT10 stabilizes Fhit mRNA through ac4C modification, enhancing its expression.

Our study identifies NAT10 as a critical regulator of CD8+ T cell-mediated immunopathology in MASH. By stabilizing Fhit mRNA, NAT10 promotes the expression of inflammatory factors, shaping the pro-inflammatory hepatic microenvironment. Targeting NAT10 presents a promising therapeutic strategy to modulate intrahepatic immunity and arrest MASH progression.