![]() ![]() Exosomes are small extracellular bilayer vesicles with diameters of 30–150 nm and contain bioactive substances similar to the components of their source cells, which makes them have similar physiological functions as the source cells. EVs are composed of exosomes and microvesicles (MVs), which are involved in physiological and pathological processes such as cell survival, immune regulation, angiogenesis, and tissue regeneration. Studies have shown that MSCs are mainly involved in tissue damage repair through the paracrine pathway, and extracellular vesicles (EVs) are the main effector components of MSCs to exert their paracrine effects. Mesenchymal stem cells (MSCs), as ideal seed cells, have achieved significant efficacy in the treatment of IBD. Thus, the results of epidemiological and clinical studies indicate the necessity to develop new treatment methods to improve the therapeutic outcome in IBD patients. Currently, effective clinical prevention and treatment of IBD remain a challenge, with existing treatments offering limited remission outcomes. IBD is mainly classified as ulcerative colitis (UC) and Crohn’s disease (CD) and has evolved with industrialization into a global disease, seriously affecting the living standards and well-being of patients. It is usually believed to be related to intestinal microbiota imbalance, environmental, and genetic factors. Inflammatory bowel disease (IBD) is a chronic and persistent intestinal inflammatory disease with unknown etiology. Abbreviations: GSH, glutathione GPX4, glutathione peroxidase 4 GSSG, oxidized glutathione DMT1, divalent metal transporter 1 ACSL4, acyl-CoA synthetase long-chain family member 4 PUFAs, polyunsaturated fatty acids ALOXs, lipoxygenases CoA, coenzyme A PL, phospholipid PLOOH, hydroperoxides, LOH, phospholipid alcohols LPO, lipid peroxidation. HucMSC-Ex-derived miR-129-5p targets ACSL4 and reduces the expression of ACSL4, an enzyme that mediates the conversion of PUFAs into phospholipids in intestinal epithelial cells, and is a positive regulator of lipid peroxidation. HucMSC-Ex can reduce the expression of DMT1 and alleviate this process. Ferric ions enter the cytosol through DMT1 and participate in lipid peroxidation. HucMSC-Ex has the ability to relieve GSH and GPX4 depletion and repair the intracellular antioxidant system. The depletion of GSH correlates with decreased GPX4, and the imbalance of the antioxidant system leads to the formation of toxic phospholipid hydroperoxide, which promotes the occurrence of ferroptosis with the participation of irons. GPX4 strongly inhibits ferroptosis by helping scavenge reactive oxygen species. System Xc − mediates the transport of extracellular cystine into the cell, which gets reduced to cysteine to participate in GSH-mediated metabolism. Mechanism of hucMSC-Ex inhibiting ferroptosis in intestinal epithelial cells. In conclusion, our results demonstrate that hucMSC-Ex relieves IBD by targeting ACSL4 with miR-129-5p to inhibit lipid peroxidation (LPO) and ferroptosis, reducing intestinal inflammation and repairing damages. We found that miR-129-5p reduces ferroptosis in intestinal epithelial cells by targeting ACSL4 to repair IBD, which provides new strategies for the prevention and treatment of IBD. In this study, we used small RNA sequencing to find that miR-129-5p was highly expressed in hucMSC-Ex, and by predicting its targeting to ACSL4, we verified the effect of miR-129-5p on mice IBD in vitro and human colonic epithelial cells (HCoEpiC) in vivo. This paper explores the role of hucMSC-Ex in the repair of IBD through the regulation of the ferroptosis signaling pathway. However, the relationship between hucMSC-Ex, IBD, and ferroptosis is unknown. Human umbilical cord mesenchymal stem cell-derived exosomes (hucMSC-Ex) are involved in cell survival, immune conditioning, and damage repair. Ferroptosis, a unique form of non-apoptotic cell death, is dependent on iron and lipoperoxidation, and has been shown to be associated with the pathogenesis of inflammatory bowel disease (IBD). ![]()
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