Duan et al. systematically delineate the spatiotemporal dynamics and key regulators of pyroptosis during MASLD progression. Hepatocyte-specific Plagl2 deletion alleviates MASH by suppressing MYD88-mediated inflammasome activation and restoring metabolic homeostasis. Pyroptosis-driven IL-1β release promotes macrophage differentiation into a phagocytosis-enhanced, JAK/STAT-activated, NASH-associated phenotype.