Oxidative Stress and Mitochondrial Dysfunction - Mediated NLRP3 Inflammasome Activation in MASLD Progression: Mechanisms and Therapeutic Implications

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is highly prevalent and may progress from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis, and hepatocellular carcinoma. Mitochondrial dysfunction and oxidative stress are central to this progression. Although increased mitochondrial oxidation may initially compensate for substrate overload, persistent lipotoxicity ultimately impairs respiratory capacity, redox homeostasis, and mitochondrial quality control. Damaged mitochondria generate mitochondrial reactive oxygen species and release danger signals, including oxidized mitochondrial DNA and cardiolipin, while defective mitophagy promotes their accumulation. Together with inflammatory priming signals, these changes facilitate NLRP3 inflammasome assembly, caspase-1 activation, IL-1β and IL-18 maturation, and gasdermin D-mediated pyroptosis. Hepatocytes are important sources of mitochondrial danger signals, whereas myeloid cells appear to be major NLRP3-dependent inflammatory and fibrogenic effectors. Hepatic stellate cells subsequently translate inflammatory and pyroptotic signals into extracellular matrix deposition. Antioxidants, mitochondria-targeted agents, metabolic therapies, and selective NLRP3 inhibitors may modulate different nodes of this axis. However, the histological benefits of currently available metabolic therapies do not establish NLRP3 inhibition as their clinical mechanism, and direct NLRP3 inhibition remains preclinical in MASH, with efficacy varying across experimental models. Future studies should integrate human-relevant models, spatial and single-cell approaches, cell-specific causal validation, and mechanistic biomarkers to identify patients most likely to benefit from targeted intervention.