Targeting KDM1A suppresses G6PD expression to induce oxidative stress and ferroptosis in TP53‐mutated liver cancer

Abstract Genomic driver mutations in tumors define specific molecular subtypes that display distinct malignancy competence, clinical outcome, and response to targeted therapy. Although TP53 mutation is predominantly detected in ∼30% hepatocellular carcinoma (HCC), current understanding of the biological traits and therapeutic strategies of this subtype has been limited. Here, we revealed that KDM1A was upregulated in the TP53‐mutant HCC and correlated with poor clinical outcomes, and that the upregulation of KDM1A conferred the tumor malignancy progression and sorafenib resistance of TP53‐mutated liver cancer. Mechanistically, KDM1A promoted the pentose phosphate pathway (PPP) reprogramming by epigenetically controlling G6PD expression which reduced the cellular reactive oxygen species (ROS) levels and lipid peroxidation, eventually leading to ferroptosis suppression and sorafenib resistance. We further demonstrated that G6PD was required for the ferroptosis suppression and tumor‐promoting role of KDM1A in TP53‐mutant HCC. Importantly, inhibition of KDM1A could synergize with sorafenib therapy in TP53‐mutated liver cancer–derived xenograft mouse models. Our study reveals that TP53‐mutated HCC represents a metabolically distinct subset, characterized by the activation of the PPP through KDM1A upregulation. This metabolic rewiring reduces ROS levels, suppressing ferroptosis and contributing to sorafenib resistance. Therefore, our findings highlight an epigenetic mechanism by which KDM1A reprograms PPP to govern oxidative stress and provide a promising therapeutic approach against HCC harboring undruggable TP53 mutations.