Lysyl oxidase-like 3 restrains mitochondrial ferroptosis to promote liver cancer chemoresistance by stabilizing dihydroorotate dehydrogenase

作者：Meixiao Zhan, Yufeng Ding, Shanzhou� Huang, Yuhang Liu, Jing Xiao, Hua Yu, Ligong Lu, Xiongjun Wang · 发表于：Nature Communications · 年份：2023 · DOI：10.1038/s41467-023-38753-6 · 被引用次数：98 · 研究领域：Microbial metabolism and enzyme function、Cancer, Hypoxia, and Metabolism、Endoplasmic Reticulum Stress and Disease

To overcome chemotherapy resistance, novel strategies sensitizing cancer cells to chemotherapy are required. Here, we screen the lysyl-oxidase (LOX) family to clarify its contribution to chemotherapy resistance in liver cancer. LOXL3 depletion significantly sensitizes liver cancer cells to Oxaliplatin by inducing ferroptosis. Chemotherapy-activated EGFR signaling drives LOXL3 to interact with TOM20, causing it to be hijacked into mitochondria, where LOXL3 lysyl-oxidase activity is reinforced by phosphorylation at S704. Metabolic adenylate kinase 2 (AK2) directly phosphorylates LOXL3-S704. Phosphorylated LOXL3-S704 targets dihydroorotate dehydrogenase (DHODH) and stabilizes it by preventing its ubiquitin-mediated proteasomal degradation. K344-deubiquitinated DHODH accumulates in mitochondria, in turn inhibiting chemotherapy-induced mitochondrial ferroptosis. CRISPR-Cas9-mediated site-mutation of mouse LOXL3-S704 to D704 causes a reduction in lipid peroxidation. Using an advanced liver cancer mouse model, we further reveal that low-dose Oxaliplatin in combination with the DHODH-inhibitor Leflunomide effectively inhibit liver cancer progression by inducing ferroptosis, with increased chemotherapy sensitivity and decreased chemotherapy toxicity.