Alpha-2-Macroglobulin Mitigates Glucocorticoid-Induced Osteonecrosis via Keap1/Nrf2 Pathway Activation

Glucocorticoids (GCs) are widely prescribed for various medical conditions, but prolonged use can result in osteonecrosis of the femoral head (ONFH), a serious condition characterized by bone tissue death due to reduced blood flow. Alpha-2-macroglobulin (A2M) is known to regulate oxidative stress and has been implicated in numerous biological processes. However, its role in GCs-induced ONFH has not been fully elucidated. This study investigates the involvement of A2M in ONFH by examining its activation of the Keap1/Nrf2 signaling pathway. Transcriptomic and proteomic analyses of patient samples with GCs-induced ONFH revealed a significant downregulation of A2M. A rat model of GCs-induced ONFH was then used to overexpress A2M, with subsequent evaluation through histopathological staining. Single-cell RNA sequencing and proteomic analysis indicated that A2M overexpression promotes the proliferation of anti-inflammatory macrophage clusters. Both in vivo and in vitro experiments demonstrated that A2M overexpression significantly alleviated ONFH symptoms by modulating oxidative stress and apoptosis via the Keap1/Nrf2 pathway. These findings underscore the critical role of A2M in mitigating GCs-induced ONFH, providing new therapeutic strategies and targets for future research.