Abstract
Over the past 30 years, the survival rate for osteosarcoma (OS) has remained stagnant, indicating persistent challenges in diagnosis and treatment. Photodynamic therapy (PDT) has emerged as a novel and promising treatment modality for OS. Despite apoptosis being the primary mechanism attributed to PDT, it fails to overcome issues such as low efficacy and resistance. Ferroptosis, a Fe2+-dependent cell death process, has the potential to enhance PDT's efficacy by increasing reactive oxygen species (ROS) through the Fenton reaction. In this study, we investigated the anti-tumor mechanism of PDT and introduced an innovative therapeutic strategy that synergistically induces apoptosis and ferroptosis. Furthermore, we have identified HERC1 as a pivotal protein involved in the ubiquitination and degradation of NCOA4, while also uncovering a potential regulatory factor involving NRF2. Ultimately, by targeting the HERC1-NCOA4 axis during PDT, we successfully achieved full activation of ferroptosis, which significantly enhanced the anti-tumor efficacy of PDT. In conclusion, these findings provide new theoretical evidence for further characterizing mechanism of PDT and offer new molecular targets for the treatment of OS.