MCT1-mediated lactate transport regulates ferroptosis in ulcerative colitis via histone lactylation

Ferroptosis, an iron-dependent type of controlled cell death caused by lipid peroxidation, contributes to intestinal epithelial injury in ulcerative colitis (UC). Monocarboxylate transporter 1 (MCT1) is a major monocarboxylate transporter in cells that regulates monocarboxylate metabolism in epithelial cells. However, its importance in the intestine and the underlying mechanisms are largely unknown. This study revealed that MCT1 is strongly associated with the degree of ferroptosis in individuals with colitis, and the potential mechanism through which MCT1 regulates ferroptosis caused by colonic damage was explored. In vivo, MCT1 inhibitors, exogenous lactate, and GPR81 knockout mice were used to investigate the underlying mechanism of MCT1-mediated lactate shuttling in DSS-induced colitis. To investigate the mechanism of MCT1 in TNF-α-induced ferroptosis, cells were subjected to MCT1 overexpression, treated with the ferroptosis inhibitor ferrostatin-1 (Fer-1), or exposed to lactate for 0, 4, 8, 12, 24, or 36 h. The results revealed that MCT1 expression was downregulated in UC patients and mouse models and was correlated with increased ferroptosis. MCT1 overexpression reduced epithelial ferroptosis in vitro, whereas MCT1 inhibition exacerbated it. Lactate treatment had the greatest protective effect at 8 h (when GPX4 expression peaked). Mechanistically, extracellular lactate activates a protective GPR81/cluster of differentiation 147 (CD147) negative feedback loop to promote the translocation of MCT1 from the cytoplasm to the plasma membrane, enhancing lactate uptake. Genetic ablation of GPR81 or inhibition of MCT1 abolished this protective feedback loop. The accumulation of intracellular lactate then promotes histone H4 lysine 16 lactylation (H4K16la). Coimmunoprecipitation (co-IP) revealed that TNF-α decreased the binding between GCN5 and H4K16la, whereas lactate therapy increased this interaction. This lactylation enhances the activity of xCT, leading to increased gene expression. This study reveals a novel MCT1-lactate-epigenetic axis that mitigates UC-related ferroptosis through feedback regulation, highlighting the critical time-dependent effect of lactate.