Extracellular vesicles derived from bone marrow mesenchymal stem cells regulate SREBF2/HMGB1 axis by transporting miR-378a-3p to inhibit ferroptosis in intestinal ischemia-reperfusion injury

Intestinal ischemia-reperfusion (II/R) injury represents a life-threatening and complex pathophysiological process that remains challenging to treat clinically, and emerging evidence suggests that ferroptosis plays an essential role in its pathogenesis. This study aimed to investigate whether extracellular vesicles derived from bone marrow mesenchymal stem cells (BMSC-EVs) can mitigate II/R-induced ferroptosis in a murine model. Using a bioinformatics database, we initially identified genes with abnormal expression patterns in II/R injury. Then, we confirmed the association between II/R injury, ferroptosis, and the HMGB1/SREBF2 axis through in vivo and in vitro experiments. To determine the role of HMGB1 in hypoxia/reoxygenation (H/R)-induced ferroptosis in Caco-2 cells, we transfected cells with either sh-HMGB1 or control sh-NC constructs and developed an H/R model in vitro. Subsequently, we examined factors regulating HMGB1-mediated ferroptosis in Caco-2 cells and assessed the effect of BMSC-EVs on this process. To further explore the mechanism underlying the protective effects of BMSC-EVs in II/R injury, we screened for miRNAs with reduced expression during II/R and verified their involvement. Among these, miR-378a-3p was identified as a candidate for regulating ferroptosis. To confirm its functional role, we treated II/R mice with BMSC-EVs overexpressing miR-378a-3p and assessed the outcomes. Our findings revealed that HMGB1, which is a key regulatory factor of ferroptosis, was significantly upregulated during II/R injury, and its knockdown alleviated H/R-induced ferroptosis in Caco-2 cells. We also found that SREBF2 directly regulates HMGB1 expression to promote H/R-induced ferroptosis in vitro. Importantly, BMSC-EVs alleviated II/R injury by suppressing ferroptosis in Caco-2 cells, and mechanistically, miR-378a-3p, a miRNA derived from BMSC-EVs, inhibited II/R-induced ferroptosis by modulating the SREBF2/HMGB1 axis. In conclusion, BMSC-EVs may exert protective effects against II/R injury by delivering miR-378a-3p, which regulates the SREBF2/HMGB1 axis to suppress ferroptosis, providing important insights into the pathological mechanisms underlying II/R injury and potential therapeutic strategies for its management.