Oral leukoplakia (OLK) is the most representative oral potentially malignant disorder, with a high risk of malignant transformation and unclear mechanisms of occurrence. Recently, photodynamic therapy (PDT) has exhibited great potential in the treatment of OLK. However, the efficacy of PDT is difficult to predict and varies from person to person. Ferroptosis-related pathways are upregulated in many cancers, and ferroptosis induction is considered to be a potential synergistic strategy for various antitumor therapies, but its role in OLK treatment remains unclear. This study aimed to determine whether ferroptosis induction can enhance the efficacy of PDT in OLK treatment. Our study revealed that solute carrier family 7 member 11 (SLC7A11), a component of a crucial amino acid transporter and a key negative regulator of ferroptosis, was found to be highly expressed in OLK patients with no response to PDT. 5-Aminolevulinic acid (ALA)-PDT is known to cause apoptosis and necrosis, but ferroptosis also occurred under ALA-PDT in OLK cells in our study. Using erastin to induce ferroptosis enhanced the efficacy of ALA-PDT on OLK cells by disrupting the antioxidant system and further elevating intracellular reactive oxygen species levels, leading to increased apoptosis. Furthermore, this combined modality also enhanced the efficacy of ALA-PDT on 4-nitroquinoline-1-oxide (4NQO)–induced OLK lesions in mice. In summary, ferroptosis induction may serve as a potential strategy to enhance the efficacy of ALA-PDT for OLK treatment.

中文翻译：

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铁死亡诱导增强 OLK 的光动力疗法疗效


口腔黏膜白斑 （OLK） 是最具代表性的口腔潜在恶性疾病，恶性转化风险高，发生机制不明。最近，光动力疗法 （PDT） 在治疗 OLK 方面显示出巨大的潜力。然而，PDT 的疗效难以预测，并且因人而异。铁死亡相关通路在许多癌症中上调，铁死亡诱导被认为是各种抗肿瘤治疗的潜在协同策略，但其在 OLK 治疗中的作用仍不清楚。本研究旨在确定铁死亡诱导是否可以增强 PDT 在 OLK 治疗中的疗效。我们的研究表明，溶质载体家族 7 成员 11 （SLC7A11） 是关键氨基酸转运蛋白的组成部分，也是铁死亡的关键负调节因子，被发现在对 PDT 无反应的 OLK 患者中高表达。已知 5-氨基乙酰丙酸 （ALA）-PDT 会导致细胞凋亡和坏死，但在我们的研究中，ALA-PDT 下 OLK 细胞也发生了铁死亡。使用 erastin 诱导铁死亡通过破坏抗氧化系统并进一步提高细胞内活性氧水平，导致细胞凋亡增加，增强了 ALA-PDT 对 OLK 细胞的疗效。此外，这种联合方式还增强了 ALA-PDT 对 4-硝基喹啉-1-氧化物 （4NQO） 诱导的小鼠 OLK 病变的疗效。总之，铁死亡诱导可能作为增强 ALA-PDT 治疗 OLK 疗效的潜在策略。