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.

为了克服化疗耐药性，需要使癌细胞对化疗敏感的新策略。在这里，我们筛选赖氨酰氧化酶 (LOX) 家族以阐明其对肝癌化疗耐药性的贡献。LOXL3 耗竭通过诱导铁死亡显着使肝癌细胞对奥沙利铂敏感。化疗激活的 EGFR 信号驱动 LOXL3 与 TOM20 相互作用，导致它被劫持到线粒体中，其中 LOXL3 赖氨酰氧化酶活性通过 S704 磷酸化得到加强。代谢腺苷酸激酶 2 (AK2) 直接磷酸化 LOXL3-S704。磷酸化的 LOXL3-S704 靶向二氢乳清酸脱氢酶 (DHODH) 并通过防止其泛素介导的蛋白酶体降解来稳定它。K344-去泛素化 DHODH 在线粒体中积累，进而抑制化疗引起的线粒体铁死亡。CRISPR-Cas9 介导的小鼠 LOXL3-S704 位点突变为 D704 导致脂质过氧化反应减少。使用晚期肝癌小鼠模型，我们进一步揭示低剂量奥沙利铂联合 DHODH 抑制剂来氟米特可通过诱导铁死亡有效抑制肝癌进展，提高化疗敏感性并降低化疗毒性。