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.

中文翻译：

---

靶向HERC1-NCOA4轴协同诱导铁死亡增强骨肉瘤光动力敏感性


过去30年来，骨肉瘤（OS）的生存率一直停滞不前，这表明诊断和治疗方面持续存在挑战。光动力疗法 (PDT) 已成为一种新颖且有前途的 OS 治疗方式。尽管细胞凋亡是PDT的主要机制，但它未能克服疗效低和耐药等问题。铁死亡是一种 Fe2+ 依赖性细胞死亡过程，通过芬顿反应增加活性氧 (ROS)，有可能增强 PDT 的功效。在这项研究中，我们研究了PDT的抗肿瘤机制，并引入了一种协同诱导细胞凋亡和铁死亡的创新治疗策略。此外，我们还发现 HERC1 是参与 NCOA4 泛素化和降解的关键蛋白，同时还发现了涉及 NRF2 的潜在调控因子。最终，通过在PDT过程中靶向HERC1-NCOA4轴，我们成功实现了铁死亡的完全激活，从而显着增强了PDT的抗肿瘤功效。总之，这些发现为进一步表征PDT机制提供了新的理论证据，并为OS的治疗提供了新的分子靶点。