Targeting Methylglyoxal Metabolism to Enhance Ferroptosis Sensitivity in Tumor Therapy

Abstract Ferroptosis, characterized by iron‐dependent lipid peroxidation, is a form of oxidative cell death increasingly recognized for its role in cancer therapy. The susceptibility of cancer cells to ferroptosis varies, highlighting the need to elucidate its underlying metabolic mechanisms. This study identifies a novel pathway in which the E3 ubiquitin ligase, praja ring finger ubiquitin ligase 1 (PJA1), mediates the proteasomal degradation of glyoxalase I (GLO1) exclusively in ferroptosis‐sensitive cancer cells. This degradation pathway is absent in ferroptosis‐resistant cells, resulting in differing management of methylglyoxal (MGO). The accumulation of MGO, as opposed to its clearance, facilitates ferroptosis by promoting the autophagic degradation of key anti‐ferroptotic proteins, specifically ferritin and glutathione peroxidase 4 (GPX4). Targeting the PJA1‐GLO1 axis through genetic and pharmacological means enhances the sensitivity of tumors to ferroptosis inducers across various preclinical models, including xenografts, orthotopic, and patient‐derived models. Additionally, clinical data demonstrate that elevated GLO1 expression is associated with poorer survival outcomes in pancreatic cancer patients. These findings suggest that modulating the MGO metabolism pathway, particularly through targeting the PJA1‐GLO1 axis, can amplify the effectiveness of ferroptosis‐inducing agents in cancer therapy.