Elmorsy Ekramy M, Al Doghaither Huda A, Al-Ghafari Ayat B, Ebrahim Neven A, Mohamed Mohamed E, Ibrahim Samah F, Elgendy Farouk S, Abdeen Ahmed
Center for Health Research, Northern Border University, Arar 91431, Saudi Arabia.
Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
Toxicol Appl Pharmacol. 2025 Oct;503:117491. doi: 10.1016/j.taap.2025.117491. Epub 2025 Aug 5.
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.
邻苯二甲酸丁基环己酯（BCP）是一种新出现的环境污染物，可通过氧化应激、线粒体功能障碍和细胞凋亡损害成骨细胞功能。本研究评估了类黄酮金丝桃苷（HYP）对BCP诱导的人成骨细胞毒性的保护作用。分子对接显示BCP和HYP与氧化应激和细胞凋亡相关蛋白有强烈结合。体外试验揭示了BCP的剂量依赖性细胞毒性，其特征为ATP生成减少、线粒体膜电位降低、线粒体复合物I和III活性降低以及线粒体自噬受抑制（PINK1/PARKIN下调）、氧化应激生物标志物升高和细胞凋亡激活（Casp-3/-8/-9、Bax/Bcl2失衡）。HYP联合处理可恢复成骨细胞活力、分泌功能和线粒体自噬，同时通过激活Nrf2/HO-1减轻氧化应激。HYP还抑制半胱天冬酶并使Bax/Bcl2比率正常化，从而防止细胞凋亡。这些发现证明了HYP的双重细胞保护作用：增强线粒体质量控制并减轻BCP诱导的氧化/凋亡损伤。该研究揭示了BCP的骨毒性机制，并将HYP定位为一种有前景的治疗方法，可通过靶向线粒体自噬、氧化还原平衡和凋亡途径来对抗环境性骨毒性，突出了基于类黄酮的干预措施在骨毒性管理中的潜力。
