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

Abstract

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.