Tumor cells exhibit a strong dependence on glucose. However, the intratumoral glucose concentration in solid tumors is considerably lower than that in adjacent non-neoplastic tissues, making adaptation to nutrient deprivation a critical requirement for tumor progression. Disulfidptosis has recently been identified as a redox-dependent form of cell death. Under conditions of glucose starvation, depletion of the NADPH exacerbates intracellular disulfide stress, resulting in aberrant disulfide bonds in actin cytoskeleton proteins. This leads to F-actin collapse and ultimately triggers disulfidptosis. Previous studies have shown that WAVE complex-mediated lamellipodia formation promotes disulfidptosis, whereas the NRF2-TrxR1 axis and endoplasmic reticulum stress suppress this process. Nonetheless, the molecular mechanisms by which tumor cells modulate this pathway to evade disulfide stress and disulfidptosis remain poorly understood.
Recently, the research group of Professor Hang-zi Chen published an article online in Nature Cell Biology titled “The mitochondrial enzyme OGDH defends against disulfidptosis by licensing METTL3-regulated NRF2 translation.” This study demonstrates that under glucose starvation, OGDH, the rate-limiting enzyme of the tricarboxylic acid cycle, mediates the succinylation of METTL3 via its metabolite succinyl-CoA. This modification enhances the ability of METTL3 to function as an m⁶A reader, recognizing m⁶A modifications within the coding region of NRF2 mRNA. Consequently, NRF2 translation is promoted, leading to upregulated TrxR1 expression and enabling melanoma cells to resist glucose starvation-induced disulfidptosis. Based on these findings, the study proposes a critical role for the HSPA9-OGDH-METTL3-NRF2 axis in melanoma adaptation to glucose deprivation.
Under glucose starvation, cancer cells cannot rely on glycolysis for sustained energy production. The researchers hypothesized that metabolic enzymes of the tricarboxylic acid cycle might facilitate cancer cell adaptation to glucose deprivation. Through knockdown of key enzymes in this cycle, they found that knockdown of either OGDH or DLST-components of the α-ketoglutarate dehydrogenase complex (OGDHC)-specifically suppressed melanoma cell survival under glucose starvation. Further experiments revealed that OGDH loss under glucose starvation led to NADPH depletion, GSSG/GSH imbalance, cystine accumulation, and disulfide bonds in actin cytoskeleton proteins, accompanied by F-actin collapse. These phenotypes were reversed by disulfide reductants such as NAC, TCEP, and DTT, but not by reactive oxygen species (ROS) scavengers or inhibitors of apoptosis, necroptosis, or ferroptosis, indicating that OGDH plays a pivotal role in counteracting glucose starvation-induced disulfidptosis.
The onset of disulfidptosis is highly dependent on disruption of intracellular redox homeostasis. Previous work has established NRF2 and its downstream target TrxR1 as key defensive factors against disulfide stress. To elucidate the downstream mechanism of OGDH, RNA sequencing and gene set enrichment analysis (GSEA) revealed that OGDH depletion blocked NRF2-regulated antioxidant pathways under glucose starvation. Glucose starvation induced upregulation of NRF2 protein and its downstream targets TrxR1 and HO1 in an OGDH enzymatic activity-dependent manner. Subsequent experiments demonstrated that under glucose starvation, OGDH-mediated regulation of NRF2 occurred independently of the canonical KEAP1-dependent ubiquitination-proteasomal pathway, and NRF2 mRNA levels remained unchanged, suggesting regulation at translational level. Polysome profiling confirmed that OGDH loss under glucose starvation increased NRF2 mRNA in monosomal fractions while reducing its association with polysomes, indicating that OGDH depletion impairs NRF2 translation.
m⁶A modification on mRNA can regulate protein translation. The researchers identified m⁶A modifications on NRF2 mRNA. METTL3 depletion suppressed NRF2 protein expression under glucose starvation. Unexpectedly, the methyltransferase activity of METTL3 was dispensable for NRF2 translation and expression. Instead, METTL3 functioned as a noncanonical m⁶A reader, recognizing m⁶A marks on NRF2 mRNA and promoting NRF2 translation by facilitating its interaction with the translation initiation factor eIF3B. Succinyl-CoA generated by OGDH served as a metabolic signal driving METTL3 succinylation, which was a prerequisite for METTL3’s m⁶A-reader function. Further investigation revealed that prolonged glucose starvation induced oxidative modification of OGDH, resulting in a time-dependent decline in its enzymatic activity accompanied by reduced intracellular succinyl-CoA. The molecular chaperone HSPA9 specifically recognized OGDH to protect it from oxidative inactivation under glucose starvation. This maintained OGDH activity and function, thereby promoting melanoma resistance to disulfidptosis.
Based on the above mechanism, the researchers further evaluated the therapeutic potential of this axis in vivo. In mouse melanoma xenograft models, interference with any component of the HSPA9-OGDH-METTL3-NRF2 axis significantly inhibited tumor growth. Both the GLUT inhibitor BAY-876 (which blocks glucose uptake) and the HSPA9 activity inhibitor MKT-077 suppressed tumor growth when administered individually, and their combination exhibited a pronounced synergistic effect. Furthermore, under a periodic fasting dietary intervention, targeted inhibition of HSPA9 also significantly suppressed tumor growth. Single-cell sequencing of clinical melanoma samples further confirmed that HSPA9 and OGDH expression negatively correlated with disulfidptosis signature genes. Survival analysis indicated that high expression of OGDH and HSPA9 was closely associated with poor prognosis in patients.
In summary, this study uncovers a novel metabolic-epitranscriptional regulatory mechanism: under glucose deprivation, melanoma cells utilize the chaperone HSPA9 to protect OGDH from oxidative inactivation. The OGDH-derived metabolite succinyl-CoA drives METTL3 succinylation, enabling METTL3 to act as an m⁶A reader that recognizes m⁶A on NRF2 mRNA, thereby promoting NRF2 translation to maintain redox homeostasis and defend against disulfidptosis. This discovery elucidates a key mechanism by which tumor cells adapt to metabolic stress and provides potential new targets for clinical intervention aimed at exploiting the metabolic vulnerabilities of tumors.
Professor Hang-zi Chen is the corresponding author of this paper. Doctoral students Xiao-yan Chen, Ke-jun Xu, Jia-xin Zhou, and Liu-zheng Wu are co-first authors. This work was supported by the National Natural Science Foundation of China.
Article link: https://www.nature.com/articles/s41556-026-02042-3
