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

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a pressing global health concern. Pyroptosis, a recently identified form of programmed cell death, is closely linked to the progression of simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH). However, the upstream transcription factors that respond to alarmins and amplify the pyroptosis effects have not been clearly illustraed. Here, we identified PLAG1 like zinc finger 2 (PLAGL2) as an amplifier of pyroptotic effects and a novel accelerator of MASH progression. Mechanistically, PLAGL2 sensitized hepatocytes to pyroptosis by transcriptionally activating MYD88 and accelerating the assembly of inflammasomes. Hepatocyte-specific PLAGL2 ablation could meliorate MASH in several dietary MASLD models by blunting hepatocyte pyroptosis, which restored differentiated identity and stablilized metabolic homeostasis. The pyroptotic release, including the paracrine secretion of IL-1b, induced macrophage chemotaxis and activation, which exhibited phenotype of NASH-associated macrophages (NAMs) through JAK-STAT pathway-dependent activation. PLAGL2 might be a potential therapeutic target for MASH management.RNA was extracted from: 1. PA+LPS treated PMHs and drug-free medium treated control (n=3);