SUMOylation-stabilized G6PD orchestrates metabolic rewiring for oxidative stress survival and chemoresistance in HCC via a PKCδ-phosphorylation trigger.

The adaptive mechanisms enabling cancer cells to withstand oxidative stress through metabolic rewiring remain poorly defined. Here, we decipher a redox-operated phosphorylation-SUMOylation relay that dynamically regulates glucose-6-phosphate dehydrogenase (G6PD) to drive hepatocellular carcinoma (HCC) progression. Oxidative stress activates protein kinase C delta (PKCδ), which phosphorylates G6PD at threonine 236 (T236), creating a steric barrier that displaces the deSUMOylase SENP1 and licenses K238 SUMOylation. This dual post-translational modification orchestrates G6PD stabilization through impaired TRIM21-mediated ubiquitination and catalytic activation via dimeric structural reorganization. Functionally, stabilized G6PD amplifies pentose phosphate pathway flux, sustaining NADPH-dependent redox balance and ribose-5-phosphate-fueled nucleotide biosynthesis to promote HCC survival under oxidative duress. Genetic disruption of K238 SUMOylation or pharmacological PKCδ inhibition synergistically enhances cisplatin efficacy by overcoming chemoresistance in preclinical models. Clinically, coordinated upregulation of G6PD and phospho-T236 correlates with aggressive HCC phenotypes and predicts poor patient outcomes. Our study identifies G6PD post-translational control as a potential metabolic vulnerability and suggests that targeted disruption of this axis may represent a promising approach to subvert redox adaptation in HCC.