Abstract
Background: Glucocorticoid-induced oxidative stress and impaired osteogenic differentiation are key pathological features of steroid-induced osteonecrosis of the femoral head (SIONFH); however, the molecular mechanisms linking oxidative stress to impaired osteogenesis remain poorly understood. Methods: We integrated multi-omics sequencing data from clinical samples and mouse models to identify key genes associated with OS and osteogenic differentiation in SIONFH. Functional enrichment and interaction network analyses were performed to explore the underlying mechanisms. In vitro and in vivo experiments were further conducted to evaluate the effects of recombinant SUZ12 protein on osteogenic differentiation and SIONFH. Results: Suppressor of zeste 12 protein (SUZ12) emerged as a potential hub gene linking oxidative stress to impaired osteogenesis. Functional enrichment and interaction network analyses suggested that SUZ12 may contribute to SIONFH pathogenesis through its involvement in polycomb repressive complex 2 (PRC2). Mechanistically, oxidative stress downregulated SUZ12 expression. In vitro and in vivo experiments demonstrated that treatment with recombinant SUZ12 protein impaired osteogenic differentiation and exacerbated SIONFH. Conclusions: Collectively, our findings identify SUZ12 as a candidate mediator linking oxidative stress to impaired osteogenesis in SIONFH and reveal a previously unrecognized mechanism whereby oxidative stress promotes SIONFH progression by downregulating SUZ12 and subsequently suppressing osteogenic differentiation. These findings advance our understanding of oxidative stress-mediated osteogenic impairment in SIONFH and highlight SUZ12 as a potential therapeutic target.