Small Intestinal Enteroendocrine Cell-Derived Exosomes Inhibit Endoplasmic Reticulum Stress-Induced Ferroptosis in Pancreatic β-Cells

Background: Type 2 diabetes mellitus (T2DM) is driven by progressive β-cell failure, wherein endoplasmic reticulum (ER) stress activates the Protein kinase R-Like ER kinase (PERK)-activating transcription factor 4 (ATF4) signaling cascade, promoting ferroptosis and accelerating β-cell dysfunction. This study investigated whether STC-1–derived exosomes (EXO) protect β-cells by modulating this pathway. Methods: A T2DM mouse model was induced via high-fat diet (HFD) feeding and streptozotocin (STZ) administration. Exosomes were extracted from STC-1 cell culture supernatants, followed by both in vitro cellular experiments and in vivo animal studies. MIN6 cells cultured under high-glucose (HG) conditions were treated with graded concentrations of STC-1-EXO or the ferroptosis inhibitor Ferrostatin-1. Cell viability was quantified using cell Counting Kit-8 (CCK-8) assay. Western blotting (WB) assessed expression of ferroptosis markers acyl-CoA synthetase long-chain family member 4 (ACSL4) and glutathione peroxidase 4 (GPX4). Ferroptotic activity was evaluated by measuring intracellular total iron concentration, malondialdehyde (MDA) content, and glutathione (GSH) levels. In vivo, T2DM mice received STC-1-EXO treatment, followed by assessment of random blood glucose, glucose tolerance, insulin sensitivity, and pancreatic histopathology with concomitant protein expression analysis. Results: In vitro, STC-1-EXO dose-dependently reversed HG-induced MIN6 cell viability loss (p p p In vivo experiments showed that compared to untreated T2DM mice, STC-1-EXO-treated mice exhibited significantly decreased random blood glucose levels and markedly improved glucose tolerance and insulin sensitivity (p p < 0.05). Conclusion: STC-1-EXO effectively ameliorates ER stress and ferroptosis in pancreatic β-cells through inhibition of the PERK-ATF4 signaling pathway, thereby improving blood glucose levels and insulin secretory function in T2DM mice. This finding provides a novel theoretical foundation and potential therapeutic strategies for exosome-based diabetes treatment.