The mitochondria enzyme OGDH defends against disulfidptosis by licensing METTL3-regulated NRF2 translation.

Disulfidptosis is a form of regulated cell death triggered by disulfide stress resulting from glucose starvation. The capacity to evade disulfidptosis is crucial for tumour cells to withstand glucose-limited environments. Here we demonstrate that OGDH, a rate-limiting enzyme in citric acid cycle, is critical for conferring resistance to disulfidptosis. High expression of HSPA9 in melanoma protects OGDH from glucose deprivation-induced oxidative inactivation, thereby ensuring OGDH-generated succinyl-CoA for METTL3 succinylation. Succinylated METTL3 recognizes m6A modification on NRF2 mRNA to license NRF2 translation, TrxR1 expression and subsequent evasion of disulfidptosis. Combined suppression of HSPA9 and glucose uptake inhibits melanoma growth in mouse models. In patients with melanoma, expressions of HSPA9 and OGDH negatively correlate with the disulfidptosis signature and are associated with an unfavourable clinical prognosis. Therefore, our findings not only highlight the dependence of melanoma cells on the HSPA9-OGDH-METTL3-NRF2 axis for disulfidptosis evasion, but also propose a combined intervention strategy for melanoma therapy.