GOT2-mediated suppression of CoQ₁₀ biosynthesis drives ferroptosis with divergent effects in lung adenocarcinoma and atherosclerosis.

Authors

Han Zhang, Xinsheng Gu, Yidan Sun, Pengcheng Chen, Qiangsheng Hu, Hao Li

Published in

Communications biology. Volume 9. Issue 1. May 29, 2026. Epub May 29, 2026.

Abstract

The roles of glutamic-oxaloacetic transaminase 2 (GOT2) in malate-aspartate shuttle (MAS), fatty acid binding/trafficking, and peroxisome proliferator-activated receptor (PPAR) delta axis have been documented. However, its function in ferroptosis remains unexplored. Here, we report that GOT2 promotes ferroptosis by disturbing mitochondrial redox homeostasis through inhibiting the synthesis of radical scavenger coenzyme Q10 (CoQ₁₀). Mechanism, by fueling MAS, GOT2 increases net influx of NADH into mitochondria and enhances aerobic respiration, increasing cellular ATP generation. The high ATP/ADP ratio inactivates adenosine 5'-monophosphate-activated protein kinase (AMPK) and PPARα, downregulating the transcription of core enzymes in CoQ₁₀ synthesis pathway (FDPS, PDSS1/2, COQ3/5/6). In lung adenocarcinoma (LUAD), high expression of GOT2 restrains tumor progression by activating ferroptosis and igniting antitumor immunity. Whereas, the activation of GOT2-mediated ferroptosis exacerbates lesion in atherosclerosis disease. Our study reveals that GOT2-AMPK-PPARα-CoQ₁₀ axis is a novel pro-ferroptosis pathway, and modulating GOT2-mediated ferroptosis suggests an intriguing method to treat LUAD and atherosclerosis.

PMID:
42215715
Bibliographic data and abstract were imported from PubMed on 16 Oct 2026.

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