Induction of Fatty Acid Oxidation Underlies DNA Damage-Induced Cell Death and Ameliorates Obesity-Driven Chemoresistance

The DNA damage response is essential for preserving genome integrity and eliminating damaged cells. Although cellular metabolism plays a central role in cell fate decision between proliferation, survival, or death, the metabolic response to DNA damage remains largely obscure. Here, this work shows that DNA damage induces fatty acid oxidation (FAO), which is required for DNA damage-induced cell death. Mechanistically, FAO induction increases cellular acetyl-CoA levels and promotes N-alpha-acetylation of caspase-2, leading to cell death. Whereas chemotherapy increases FAO related genes through peroxisome proliferator-activated receptor alpha (PPAR alpha), accelerated hypoxia-inducible factor-1 alpha stabilization by tumor cells in obese mice impedes the upregulation of FAO, which contributes to its chemoresistance. Finally, this work finds that improving FAO by PPAR alpha activation ameliorates obesity-driven chemoresistance and enhances the outcomes of chemotherapy in obese mice. These findings reveal the shift toward FAO induction is an important metabolic response to DNA damage and may provide effective therapeutic strategies for cancer patients with obesity. The study identifies a novel metabolic response to DNA damage involving the induction of mitochondrial fatty acid oxidation (FAO). Obesity impedes the upregulation of FAO, causing resistance to chemotherapy. Restoration of FAO overcomes obesity-driven chemoresistance, enhancing chemotherapy outcomes. These findings underscore FAO induction as a crucial metabolic response to DNA damage, offering potential therapeutic strategies for obese cancer patients.image