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. This study aimed to explore whether CoQ10 could mitigate intestinal IRI by suppressing ferroptosis. 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. 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. Our study reveals a crucial role of CoQ10 in ferroptosis and highlights the potential of CoQ10 as a promising target for intestinal IRI treatment.

Adverse childhood experiences (ACEs) are related to an increased risk of gastrointestinal disorders. However, whether uric acid (UA) affects the development of digestive diseases and its role in the link between ACEs and digestive diseases have not been fully studied. All data for this longitudinal cohort study came from the China Health and Retirement Longitudinal Study (CHARLS). Cox proportional hazards regression model was applied to assess the relationship between ACEs or UA and digestive diseases and the mediating effect of UA between ACEs and digestive diseases. Lastly, subgroup analyses were performed by demographic characteristics and health status grouping. The study included 3666 volunteers, of whom 617 had digestive disorders. Using Cox proportional hazards regression model, we analyzed the association between ACE and digestive diseases, and found that household mental illness, and living in an unsafe neighborhood were all obviously associated with disease incidence. Studies have also demonstrated an association between UA and digestive disorders. In the mediation analysis, we found that unsafe neighborhood had a negative indirect effect on digestive system diseases through UA, and this mediating effect was shown to have comparable results in the subgroup analyses. We found evidence that ACEs and UA levels are associated with the development of digestive diseases, and that UA levels influence the relationship between one of the ACEs, namely unsafe neighborhood and digestive disease. Further research should address the underlying mechanisms and interventions to prevent childhood adversities and their devastating effects on health.