Xie Minyue, Gu Xiang, Zhao Zheng, Hua Yu, Wu Qianru, Tang Yizhen, Zhuang Ai, Ge Shengfang, Jia Renbing, Yu Jie, Ruan Jing, Fan Xianqun
Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.
iScience. 2025 Jun 21;28(8):112972. doi: 10.1016/j.isci.2025.112972. eCollection 2025 Aug 15.
Uveal melanoma (UM) is the most common primary intraocular malignancy in adults, and it is associated with a poor prognosis due to the lack of effective targeted therapies. Artemisinin (ARS), a widely used antimalarial drug, has demonstrated anti-tumor effects in several types of cancer, including UM. However, these effects are primarily observed at high concentrations, which restricts its broader use. Our study reveals mitochondrial uncoupler agents as synergistic partners with DHA in treating UM, both and . Specifically, the combination of DHA and CCCP, a representative mitochondrial uncoupler, induced endoplasmic reticulum (ER) stress by enhancing the binding of ATF4 and CHOP to the SESN2 promoter region. This ER stress subsequently activated autophagic cell death, augmenting UM cell eradication. Our findings suggest that combining DHA with mitochondrial protonophore uncouplers inhibits UM proliferation, underscoring the therapeutic promise of this approach for UM treatment.
葡萄膜黑色素瘤（UM）是成人中最常见的原发性眼内恶性肿瘤，由于缺乏有效的靶向治疗，其预后较差。青蒿素（ARS）是一种广泛使用的抗疟药物，已在包括UM在内的几种癌症中显示出抗肿瘤作用。然而，这些作用主要在高浓度下观察到，这限制了其更广泛的应用。我们的研究揭示线粒体解偶联剂是二十二碳六烯酸（DHA）治疗UM的协同伙伴。具体而言，DHA与典型的线粒体解偶联剂羰基氰-间氯苯腙（CCCP）的组合，通过增强激活转录因子4（ATF4）和 Chop 同源蛋白（CHOP）与硒蛋白N2（SESN2）启动子区域的结合来诱导内质网（ER）应激。这种ER应激随后激活自噬性细胞死亡，增强UM细胞的清除。我们的研究结果表明，DHA与线粒体质子载体解偶联剂联合使用可抑制UM增殖，突出了这种方法在UM治疗中的治疗前景。
