Hyperoside protects human osteoblasts from phthalate-induced mitochondrial dysfunction, oxidative stress, and...

Butyl cyclohexyl phthalate (BCP), an emerging environmental contaminant, impairs osteoblast function via oxidative stress, mitochondrial dysfunction, and apoptosis. This study evaluated hyperoside (HYP), a flavonoid, for its protective effects against BCP-induced toxicity in human osteoblasts. Molecular docking showed strong binding of BCP and HYP to oxidative stress- and apoptosis-related proteins. In vitro assays revealed BCP's dose-dependent cytotoxicity, marked by decreased ATP production, mitochondrial membrane potential, mitochondrial complexes I and III activities, and suppressed mitophagy (PINK1/PARKIN downregulation), elevated oxidative stress biomarkers, and activated apoptosis (Cas-3/-8/-9, Bax/Bcl2 imbalance). HYP co-treatment restored osteoblast viability, secretory function, and mitophagy while reducing oxidative stress via Nrf2/HO-1 activation. HYP also inhibited caspases and normalized Bax/Bcl2 ratios, preventing apoptosis. These findings demonstrate HYP's dual cytoprotective role: enhancing mitochondrial quality control and mitigating BCP-induced oxidative/apoptotic damage. The study unveils BCP's osteotoxic mechanisms and positions HYP as a promising therapeutic to counteract environmental bone toxicity by targeting mitophagy, redox balance, and apoptotic pathways, highlighting the potential of flavonoid-based interventions in osteotoxicity management.