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，有可能通过芬顿反应增加活性氧 (ROS) 来增强 PDT 的功效。在本研究中，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。版权所有 © 2024 作者。由 Elsevier B.V. 出版。保留所有权利。

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.Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.