Hepatocyte PLAGL2 deficiency alleviates MASH through MYD88-licensed inactivation of inflammasome

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a pressing global health concern. The transition to metabolic dysfunction-associated steatohepatitis (MASH) is characterized by pyroptosis-driven inflammation. However, the spatiotemporal regulation of this process remains elusive. Here, we identify PLAG1-like zinc finger 2 (PLAGL2) as a potent amplifier of pyroptotic signaling and a key driver accelerating MASH progression. Mechanistically, PLAGL2 sensitizes hepatocytes to pyroptosis by transcriptionally activating Myeloid Differentiation Primary Response 88 (MYD88), thereby facilitating inflammasome assembly. Hepatocyte-specific Plagl2 knockout ameliorates MASH in multiple dietary MASLD models. This effect occurs through the attenuation of hepatocyte pyroptosis, which restores hepatocyte identity and stabilizes metabolic homeostasis. The pyroptotic release induces macrophage chemotaxis and activation. These macrophages exhibit a phenotype characteristic of NASH-associated macrophages (NAMs) via JAK-STAT pathway-dependent activation. Interleukin-1β (IL-1β) released by pyroptotic hepatocytes functions as the key mediator activating JAK-STAT signaling. PLAGL2 might be a potential therapeutic target for MASH management.