Targeting pyroptosis in metabolic dysfunction-associated steatotic liver disease: from molecular mechanisms to therapeutic innovation.

Metabolic dysfunction-associated steatotic liver disease (MASLD) represents the most common chronic liver disease globally. Pyroptosis, a programmed inflammatory cell death mediated by inflammasome activation and gasdermin proteins, plays a central role in driving hepatic inflammation and injury in MASLD. This mini-review summarizes the mechanistic contributions of pyroptosis to MASLD progression, focusing on how key molecules (e.g., NLRP3 inflammasome, caspases, and GSDMD) integrate lipotoxic signals to execute hepatocyte lysis and pro-inflammatory mediator release. We also categorize and discuss emerging intervention strategies targeting pyroptosis, including direct NLRP3 inflammasome inhibition, blockade of the caspase-1/GSDMD axis, modulation of upstream signaling pathways, and multi-mechanistic approaches such as autophagy activation. Despite promising therapeutic potential, challenges remain, such as mechanistic complexity, model limitations, and a lack of clinically available drugs. Future directions should emphasize multi-omics studies, development of liver-targeted delivery systems, and clinical translation of biomarkers and specific inhibitors to advance precise MASLD therapy.