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

Meixiao Zhan, Yufeng Ding (), Shanzhou Huang, Yuhang Liu, Jing Xiao, Hua Yu (), Ligong Lu () and Xiongjun Wang ()
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Meixiao Zhan: Zhuhai People’s Hospital, Zhuhai Hospital affiliated with Jinan University, Zhuhai
Yufeng Ding: Guangzhou University
Shanzhou Huang: Guangdong Academy of Medical Sciences
Yuhang Liu: Guangzhou University
Jing Xiao: Zhuhai People’s Hospital, Zhuhai Hospital affiliated with Jinan University, Zhuhai
Hua Yu: Guangzhou University
Ligong Lu: Zhuhai People’s Hospital, Zhuhai Hospital affiliated with Jinan University, Zhuhai
Xiongjun Wang: Guangzhou University

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-38753-6

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