biostudies-literatureZhang XNatural Science Foundation of Jilin Province of ChinaNatural Science Foundation of Jilin Provincee05356https://www.ebi.ac.uk/biostudies/studies/S-EPMC12561271biostudies-literatureUnknown12(40)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, specificalAdvanced science (Weinheim, Baden-Wurttemberg, Germany)Targeting Methylglyoxal Metabolism to Enhance Ferroptosis Sensitivity in Tumor Therapy.PMC12561271YDZJ202501ZYTS075Liu JLiu ZKang RHan LZhang XDu XDai ETang DWang ZYu HfalseTargeting Methylglyoxal Metabolism to Enhance Ferroptosis Sensitivity in Tumor Therapy.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, specifical2025-01-01T00:00:00Z2025 Oct2026-06-05T09:33:55.859Z2026-05-15T03:12:47.922ZS-EPMC125612714090856410.1002/advs.202505356