Ergothioneine promotes osteogenesis and angiogenesis through PI3K/AKT pathway and prevents glucocorticoid-induced osteonecrosis of the femoral head.

Osteonecrosis of the femoral head (ONFH) has a high incidence worldwide, yet effective treatments remain lacking. Oxidative stress and mitochondrial dysfunction are closely associated with ONFH development. Ergothioneine (EGT) is a potent antioxidant that can target various organs; however, its potential role in ONFH remains elusive. This study aimed to evaluate the protective effects of EGT against steroid-induced ONFH and to explore the underlying mechanisms involved. Murine bone marrow mesenchymal stem cells (BMMSCs) and human umbilical vein endothelial cells (HUVECs) were treated with EGT following dexamethasone induction. Subsequent experiments assessed cell viability and functional changes in each group. A steroid-induced rat model of ONFH was established, and the therapeutic efficacy of EGT was verified through imaging and histological analyses. Dexamethasone disrupted both the structure and function of mitochondria and induced apoptosis in BMMSCs and HUVECs. In contrast, EGT treatment activated the protein kinase B (AKT)/phosphoinositide 3-kinase (PI3K) pathway under steroid stimulation, and the cellular damage was reversed. Moreover, in the steroid-induced ONFH rat model, EGT supplementation reduced bone structural destruction and the expression of degenerative biomarkers, along with maintaining angiogenic and osteogenic marker levels. EGT exerts a protective effect against steroid-induced mitochondrial dysfunction and apoptosis by activating the AKT/PI3K-signaling pathway and maintaining osteogenesis and angiogenesis during ONFH development. These findings suggest its potential as a therapeutic agent for treating steroid-induced ONFH. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-026-38834-8.