A recent study published in Scientific Reports on March 15, 2025, has explored the potential role of the PI3K/AKT signaling pathway and cuproptosis in the treatment of steroid-induced osteonecrosis of the femoral head (SIONFH). This condition, prevalent among patients undergoing steroid treatment for various chronic conditions, leads to debilitating bone necrosis, and current treatment options remain limited.
Researchers conducted analyses on femoral head specimens from SIONFH patients, utilizing data-independent acquisition (DIA) proteomics to identify protein expressions associated with cuproptosis—an oxidatively induced form of cell death linked to disruptions caused by copper toxicity. They discovered key proteins, such as DLAT, PDHB, and SLC25A3, to be downregulated, indicating significant metabolic and osteogenic impairment due to the influence of glucocorticoids like dexamethasone (DEX).
Invoked copper toxicity resulted from sustained DEX treatment manifested as increased copper ion concentration, showcasing reductions in alkaline phosphatase (ALP) activity and osteogenic markers like RUNX2 and BMP2. These findings imply cuproptosis directly impairs osteoblast functionality and survival, hinting at its role as part of the underlying mechanisms confounding SIONFH.
Through additional experiments, the researchers activated the PI3K/AKT pathway using the agonist 740Y-P. Notably, they recorded significant restoration of FDX1 protein levels and partial recovery of osteogenic capabilities post-treatment, underscoring the protective capacity afforded by PI3K/AKT activation against glucocorticoid-induced cellular death.
Further validation was conducted with rat models. Results from micro-computed tomography (Micro-CT) evaluations demonstrated improved bone volume and trabecular thickness metrics among 740Y-P treated rats, contrasting starkly against the untreated experimental group. Histological examinations corroborated the restoration of osteoblast activity indicated by higher RUNX2 expressions.
The results suggest not only the possibility of targeting the PI3K/AKT signaling pathway to mitigate the effects of SIONFH but also contribute to our broader comprehension of copper metabolism dysregulation's impact on bone health.
The relevance of this study is underscored by its multifaceted approach, engaging patient data alongside experimental methodologies to garner insights to potentially reshape treatment paradigms for patients suffering from steroid-related bone disorders. The authors concluded, “The activation of the PI3K/AKT signaling pathway can restore the expression of FDX1 and rescue the impaired osteogenic capacity caused by cuproptosis.”