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.
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Funding
This research was supported by the National Natural Science Foundation of China (Grant no. 82403099), the Key Discipline of Shanghai Health System Funding Project (Grant no. 2024ZDXK0028), the Xuhui Healthcare System Peak Discipline Construction Funding Project (Grant no. SHXHZDXK202305), the Construction of Key Medical Disciplines in Xuhui District (Grant no. SHXHZDXK202306), and the Youth Project of Medical Research in Xuhui District (Grant no. SHXH202433).
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Zhang, H., Gu, X., Sun, Y. et al. GOT2-mediated suppression of CoQ10 biosynthesis drives ferroptosis with divergent effects in lung adenocarcinoma and atherosclerosis. Commun Biol (2026). https://doi.org/10.1038/s42003-026-10365-y
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DOI: https://doi.org/10.1038/s42003-026-10365-y
