Astaxanthin Protects Against Ferroptosis and Oxidative Stress via Retinoic Acid-Mediated SLC7A11 Regulation by Lepagella muris

Oxidative stress and ferroptosis are central to the pathogenesis of many diseases, including those characterized by intestinal damage, where excessive lipid peroxidation and iron accumulation trigger cellular dysfunction. In this study, we investigate the protective effects of astaxanthin (ASTA), a potent antioxidant carotenoid, against dexamethasone (DEX)-induced oxidative stress and ferroptosis in the intestine. We demonstrate that ASTA supplementation significantly restores antioxidant defenses, enhancing key antioxidant enzymes. Furthermore, ASTA alleviates ferroptosis by upregulating GPX4 expression and reducing iron accumulation, thereby mitigating cellular damage. Using 16S rRNA sequencing and metagenomic analysis, we identify shifts in gut microbiota composition induced by ASTA, with a notable enrichment of Lepagella muris and other beneficial bacteria. These shifts correlate with the upregulation of retinol metabolism pathways, particularly those involving enzymes such as beta-carotene monooxygenase 1 (BCMO1) and aldehyde dehydrogenase (ALDH). Metabolomic profiling further confirms that L. muris metabolizes ASTA to promote retinoic acid biosynthesis, which targets key ferroptosis-related genes, including SLC7A11, thereby inhibiting the activation of the ferroptosis pathway. RETINOIC ACID-mediated activation of SLC7A11 restores cellular redox balance, protecting against ferroptosis. Our findings provide mechanistic insights into how ASTA, through gut microbiota-mediated retinoic acid biosynthesis, modulates oxidative stress and ferroptosis pathways, offering a novel therapeutic approach for diseases associated with these processes. These results underscore the potential of microbiota-targeted interventions to enhance the efficacy of antioxidant therapies in treating oxidative stress-induced disorders.