Jiao-Tai-Wan improves pancreatic β cell function by regulating ferroptosis via the Nrf2/NQO1 signaling pathway

BACKGROUNDFerroptosis contributes to pancreatic β cell dysfunction in type 2 diabetes mellitus (T2DM).Jiao-Tai-Wan (JTW) can significantly treat hyperglycemia, but its specific mechanism is incompletely understood.In this study, we hypothesized that JTW improves pancreatic β cell function in T2DM by suppressing ferroptosis through activation of the Nrf2/NQO1 signaling pathway. AIMTo investigate the anti-ferroptotic mechanism of JTW in T2DM using network pharmacology and experimental validation in vivo and in vitro.METHODS Network pharmacology and weighted gene co-expression network analysis (WGCNA) were used to identify potential active compounds and core targets of JTW in treating T2DM.T2DM mice were administered JTW or metformin for 8 weeks to evaluate fasting plasma glucose (FPG), insulin secretion, pancreatic morphology, ferroptosis markers, and Nrf2/NQO1 signaling pathway.In vitro, high glucose-treated MIN6 cells were exposed to JTW-containing serum, with or without the Nrf2 inhibitor ML385.A separate group was treated with the ferroptosis inhibitor ferrostatin-1 (Fer-1).Cell viability, proliferation, glucose-stimulated insulin secretion, ferroptosis markers and Nrf2/NQO1 signaling pathway activity were assessed.RESULTS A total of 134 intersecting targets between JTW and T2DM were identified, with enrichment analysis highlighting ferroptosis as a key pathway.Integration of WGCNAderived brown module genes, drug-disease targets, and the ferroptosis database 4 / 51 yielded 4 core targets, among which NQO1 exhibited higher binding energies with principal bioactive alkaloids in Coptis chinensis.In vivo, JTW significantly reduced FPG, improved glucose tolerance and insulin secretion, and ameliorated pancreatic islet morphology in T2DM mice.JTW also suppressed ferroptosis-related biochemical indicators and upregulated Nrf2, NQO1, and HO-1 expression in pancreatic tissues.These findings were corroborated in vitro, where JTW-containing serum protected MIN6 cells against glucotoxicity-induced ferroptosis.Notably, the protective effects of JTW on ferroptosis-related indicators were comparable to those of Fer-1, while the Nrf2 inhibitor ML385 reversed the protective effects of JTW.CONCLUSION JTW protects pancreatic β cell function by inhibiting ferroptosis through activation of the Nrf2/NQO1 signaling pathway, providing a mechanistic basis for its antidiabetic effects.