光动力疗法 (PDT) 是一种有效的肿瘤治疗方法，涉及使用光敏剂，从特定波长肿瘤照射后能量吸收产生的分子氧中产生细胞毒性 1O2 [活性氧 (ROS)]。铁死亡是由谷胱甘肽过氧化物酶 4 (GPX4) 抗氧化系统破坏引起的，导致脂质过氧化。我们假设他拉泊芬钠光动力疗法 (TS-PDT) 产生的 ROS 会通过脂质过氧化的积累导致铁死亡。与铁死亡抑制剂 (ferrostatin-1: Fer-1) 联合使用 TS-PDT 处理的细胞进行细胞活力测定）或铁死亡诱导剂（咪唑酮erastin：IKE，Ras选择性致死3：RSL3）进行。研究了 TS-PDT 处理的细胞中脂质过氧化、GPX4 抗氧化系统和胱氨酸/谷氨酸逆向转运蛋白（系统 xc-）活性的积累。在异种移植小鼠中，检测了 TS-PDT 与铁死亡诱导剂（IKE 或索拉非尼）联合的抗肿瘤作用。TS-PDT 诱导的细胞死亡被 Fer-1 部分抑制，并伴有脂质过氧化。 TS-PDT 与 IKE 或 RSL3 联合增强了细胞死亡的诱导。 TS-PDT 通过系统 xc- 抑制胱氨酸摄取活性。在体内，TS-PDT 与铁死亡诱导剂（IKE 或索拉非尼）联合使用可缩小肿瘤体积。本研究发现，TS-PDT 诱导铁死亡的机制是产生的 ROS 直接导致脂质过氧化，并抑制 xc- 系统。 ，并且铁死亡诱导剂与 TS-PDT 的组合增强了 TS-PDT 的抗肿瘤作用。我们的研究结果表明，铁死亡诱导疗法与 PDT 相结合可能有益于癌症患者。© 2023。日本胃肠病学会。

Photodynamic therapy (PDT) is an effective tumor treatment that involves the administration of a photosensitizer to generate cytotoxic 1O2 [reactive oxygen species (ROS)] from molecular oxygen that is produced from energy absorption following tumor irradiation at specific wavelengths. Ferroptosis is induced by the disruption of the glutathione peroxidase 4 (GPX4) antioxidant system, leading to lipid peroxidation. We hypothesized that talaporfin sodium-photodynamic therapy (TS-PDT)-generated ROS would lead to ferroptosis via accumulation of lipid peroxidation.Cell viability assay in TS-PDT-treated cells in combination with a ferroptosis inhibitor (ferrostatin-1: Fer-1) or ferroptosis inducers (imidazole ketone erastin: IKE, Ras-selective lethal 3: RSL3) was performed. Accumulation of lipid peroxidation, GPX4 antioxidant system and cystine/glutamate antiporter (system xc-) activity in TS-PDT-treated cells was investigated. In xenograft mice, the antitumor effect of TS-PDT in combination with ferroptosis inducers (IKE or sorafenib) was examined.TS-PDT-induced cell death was partly suppressed by Fer-1 and accompanied by lipid peroxidation. TS-PDT combined with IKE or RSL3 enhanced the induction of cell death. TS-PDT inhibited cystine uptake activity via system xc-. In vivo, the combination of TS-PDT and ferroptosis inducers (IKE or sorafenib) reduced tumor volume.This study found that the mechanism underlying TS-PDT-induced ferroptosis constitutes direct lipid peroxidation by the generated ROS, and the inhibition of system xc-, and that the combination of a ferroptosis inducer with TS-PDT enhances the antitumor effect of TS-PDT. Our findings suggest that ferroptosis-inducing therapies combined with PDT may benefit cancer patients.© 2023. Japanese Society of Gastroenterology.