In the present study, we revealed that the IL-21R-STAT1-c-Jun/c-Fos-IgA regulatory pathway was activated during MASH-driven hepatocarcinogenesis, leading to the induction of immunosuppressive IgA+ B cells, and thereby inhibited CTL activation and eventually facilitated MASH-driven HCC in vivo. Here, IL21R is linked to hepatocellular carcinoma.