Zoledronic acid induces ferroptosis by upregulating POR in osteosarcoma.

Abstract

Osteosarcoma, usually originating in the stroma, is the most common primary bone cancer in adolescents, and its prognosis is poor. Surgery,adjuvant and neoadjuvant chemotherapy andradiationtherapyare not satisfactoryatthepresenttime. Therefore, itiscriticalto develop novel therapeutic strategies to improve the quality of life and long-term survival rate of osteosarcoma patients. In this study, we discovered that zoledronic acid (ZOL) dramatically increased cell deathin osteosarcoma cells, and this cytotoxicity was greatly reversed byliproxstatin-1 (a ferroptosis inhibitor). ZOL alsohadanobviouseffectonlipid peroxidation and reactive oxygen species(ROS), which suggested that ZOL most certainly induces ferroptosis in osteosarcoma cells. In addition, we further found thatZOLincreasescytochrome P450 oxidoreductase (POR) expression dose dependently in osteosarcoma cell lines. Knockdown of POR attenuated ZOL-induced cytotoxicity and attenuated the effect of ferroptosis in osteosarcoma cells, which indicated that POR plays an important role in ferroptosis. Moreover, we also found that ZOL inhibits osteosarcoma growth in vivo. Our findings suggest that ZOL induces ferroptosis by upregulating POR expression to increase ROS levels and upregulate lipid peroxidation levels in osteosarcoma cells. PORmay be used asa therapeutictarget to inhibit osteosarcoma.