Nlrp12-driven PANoptosis exacerbates liver injury in ConA-induced autoimmune hepatitis.

Abstract

Autoimmune hepatitis (AIH) involves chronic liver injury from abnormal immune responses, leading to hepatocyte death and inflammation. Currently, the role of pyroptosis in AIH has not been fully elucidated. Emerging evidence indicates that Nlrp12, a cytosolic sensor of damage-associated molecular patterns (DAMPs), participates in inflammasome assembly and pyroptotic signalling. Therefore, this study aims to investigate the role of Nlrp12 in AIH. Using a concanavalin A (ConA)-induced AIH mouse model, we observed that ConA challenge significantly upregulated Nlrp12 expression in liver tissues. Genetic ablation of Nlrp12 improved survival rates, lowered serum aminotransferase levels, reduced pro-inflammatory cytokine production, and ameliorated histological liver damage. Further studies revealed that Nlrp12 drives the assembly of PANoptosomes (including ASC, RIPK3, and Caspase-8), promoting the release of PANoptosis-related proteins and inflammatory factors. The RIPK3 inhibitor GSK-872 blocked PANoptosome formation, mitigating liver injury and inflammation. These findings unveil a previously unrecognized role for Nlrp12 in aggravating immune-mediated liver injury via PANoptosis activation, highlighting the Nlrp12-PANoptosis axis as a promising therapeutic target for AIH.