Targeting the Pyroptosis-Mitochondrial Homeostasis Crosstalk: Astaxanthin Attenuates Alcohol-Induced Inflammatory Liver Injury via Inhibition of cGAS-STING Signaling

Emerging research evidence has established the critical role of inflammatory cascades in the development and progression of alcoholic liver injury with hepatocellular death serving as a principal driver. Notably, the dysregulated interplay between mitochondrial homeostasis and pyroptosis is primarily responsible for the alcohol-induced aberrant liver immune microenvironment, characterized by nonresolving inflammation. Given the considerable limitations in the current treatment for alcoholic steatohepatitis (ASH), it is imperative to explore targeted nutritional interventions as alternative therapies. Here, we established an ASH model with C57BL/6J mice and demonstrated that astaxanthin (AST) administration significantly protected against alcohol-induced inflammatory liver injury through dual mechanisms: 1) suppression of hepatocyte pyroptosis by inhibiting the NLRP-3/Caspase/GSDMD signaling axis and 2) mitigation of mitochondrial dysfunction evidenced by structural membrane integrity restoration and redox homeostasis rebalancing. Mechanistically, AST intervention impeded the cytoplasmic translocation of mitochondrial DNA (mtDNA), thereby concurrently inhibiting AIM2 inflammasome activation and cGAS/STING signaling. In vitro studies further confirmed dose-dependent attenuation of alcohol-induced hepatotoxicity by AST, marked by reduced pyroptotic cell death and diminished proinflammatory cytokine secretion (IL-1β, IL-18). Mitochondrial protection was further evidenced through restored membrane potential (ΔΨm), decreased cytoplasmic Cytochrome <i>C</i> release, and attenuated mtDNA leakage. Moreover, we identified a novel molecular interaction, wherein AST competitively binds lipid-binding motifs within the β1-β2 loop of the GSDMD-N-terminal domain, potentially interfering with pyroptotic pore formation. Further overexpression experiments confirmed the improvement effect of AST on pyroptosis induced by GSDMD-N pore formation. Concurrently, AST exhibited potent antioxidant effects against alcohol-induced cardiolipin peroxidation, suggesting dual therapeutic modalities targeting both pyroptotic execution and mitochondrial membrane stabilization. Collectively, our findings identify AST as a promising candidate for therapeutic interventions against alcoholic inflammatory liver injury through coordinated modulation of the pyroptosis-mitochondrial homeostasis crosstalk, offering novel insights into nutritional intervention strategies for alcohol-related liver pathologies.