FSP1 reduces exogenous coenzyme Q10 and inhibits ferroptosis to alleviate intestinal ischemia–reperfusion injury

INTRODUCTION: Intestinal ischemia-reperfusion injury (IRI) is a critical condition often requiring emergency intervention. Ferroptosis, a form of regulated cell death driven by phospholipid peroxidation, plays a central role in its pathogenesis. OBJECTIVE: This study aimed to explore whether CoQ10 could mitigate intestinal IRI by suppressing ferroptosis. METHODS: We analyzed serum CoQ10 levels and inflammatory cytokines in patients with mesenteric artery embolism. In mice, intestinal IRI was induced by transient superior mesenteric artery ligation following two weeks of CoQ10 pretreatment. Histology, ELISA, immunoblotting, and RNA sequencing were used to assess therapeutic effects. To explore mechanisms, we used CRISPR/Cas9 to generate FSP1 and COQ2 knockouts in enterocytes, along with targeted metabolomics and co-autoxidation assays. In vivo loss of FSP1 function was induced by AAV9 to evaluate its role in CoQ10-mediated protection. RESULTS: Utilizing both our own and publicly available intestinal IRI cohorts, we identified a correlation between elevated CoQ10 levels and reduced systemic inflammation, along with decreased oxidized lipid accumulation in ischemia-reperfusion-affected small intestines. Transcriptomic enrichment analyses and biochemical assays demonstrated that CoQ10 supplementation effectively mitigates IRI by modulating lipid metabolism and inhibiting lipid peroxidation and ferroptosis. To elucidate the mechanism of action of CoQ10 against lipid peroxidation and ferroptosis, we established an in vitro ferroptosis-associated intestinal IRI model using enterocytes, which revealed that the CoQ10-mediated suppression of ferroptosis is dependent on FSP1. Targeted metabolomics analyses and co-autoxidation assays indicated that FSP1 suppresses ferroptosis by reducing CoQ10, thereby preventing phospholipid peroxidation. Loss of function FSP1 generated by genetic and pharmacological mechanisms in enterocytes or mouse intestines led to a decrease in the levels of reduced CoQ10, negating the therapeutic effects of CoQ10 on intestinal IRI. CONCLUSION: Our study reveals a crucial role of CoQ10 in ferroptosis and highlights the potential of CoQ10 as a promising target for intestinal IRI treatment.