ABSTRACT Ferroptosis, an iron‐dependent form of regulated cell death, has been implicated in the pathogenesis of type 2 diabetes (T2DM), but its underlying mechanisms remain unclear. Here, we identify cystathionine β‐synthase (CBS), a rate‐limiting enzyme in the trans‐sulfuration pathway, as a critical metabolic regulator linking glutathione (GSH) homeostasis to ferroptosis sensitivity in T2DM. Multi‐omics integration revealed marked disruption of the ferroptosis pathway and GSH metabolism in patients with T2DM and highlighted CBS as a ferroptosis‐associated gene strongly correlated with glycemic traits. Population‐level analyses revealed that CBS expression was positively associated with GSH and negatively with plasma ferritin, and Mendelian randomization supported a causal protective effect of CBS on T2DM risk. In vitro, high glucose reduced CBS expression in MIN6 cells, whereas CBS overexpression increased GSH, restored antioxidant capacity, suppressed Fe 2+ accumulation, and shifted ferroptosis markers toward an anti‐ferroptotic profile, accompanied by improved β‐cell functional gene expression. Notably, inhibition of GSH synthesis largely abolished the protective effects of CBS, indicating that the anti‐ferroptotic function is GSH dependent. Mechanistically, cystathionine γ‐lyase (CTH) was identified as an essential coregulator of CBS. Disruption of CTH greatly weakened CBS‐driven improvements in GSH maintenance, iron–redox homeostasis, and β‐cell function, establishing a functional CBS–CTH–GSH axis. In summary, our findings identify that CBS can protect β‐cells from ferroptotic injury and functional decline under glucotoxic stress and highlight the CBS–CTH–GSH axis as a promising β‐cell‐targeted intervention point for delaying or preventing T2DM progression.
Li et al. (Fri,) studied this question.