Hydrogen activates ACOD1-itaconate pathway to ameliorate steroid-associated osteonecrosis

Steroid-associated osteonecrosis (SAON) remains a challenging clinical condition as there are few effective preventive measures. This study investigates the effects of hydrogen (H₂) administrated via saturated hydrogen-rich water (HRW) in mice received high dose of glucocorticoids (for inducing SAON model). Here we find that HRW treatment significantly reduces osteocyte apoptosis, improves deteriorated trabecular architecture, increases osteoblast numbers and the bone formation, while decreases osteoclast numbers and the bone resorption. Additionally, HRW-treated mice exhibit improved serum lipid profiles, including decreased levels of low-density lipoprotein (LDL), triglycerides (TG), and total cholesterol (T-CHO), as well as reduced lipid accumulation. HRW treatment also enhances blood perfusion and increases formation of type H vessels in SAON mice. We further demonstrate that HRW shifts the polarization of macrophages from M1 to M2 phenotype and suppresses inflammatory marker TNF-α. RNA sequencing data and subsequent validation reveal that HRW upregulates ACOD1 mRNA and protein levels in bone tissues. The protective effects of HRW are mimicked by supplementation with the itaconate derivative dimethyl itaconate in a dose-dependent manner, highlighting the importance of the ACOD1-itaconate pathway in the prevention of SAON by HRW. These findings indicate that HRW ameliorates SAON by modulating the ACOD1-itaconate pathway, presenting a novel avenue for the cost-effective prevention of osteonecrosis.