Famurewa Ademola C, Akhigbe Roland E, George Mina Y, Adekunle Yemi A, Oyedokun Precious A, Akhigbe Tunmise M, Fatokun Amos A
Department of Medical Biochemistry, Faculty of Basic Medical Sciences, College of Medical Sciences, Alex Ekwueme Federal University Ndufu-Alike, Ikwo, Nigeria.
Centre for Natural Products Discovery, School of Pharmacy and Biomolecular Sciences, Faculty of Science, Liverpool John Moores University, Byrom Street, Liverpool, L3 3AF, UK.
Naunyn Schmiedebergs Arch Pharmacol. 2025 May;398(5):4747-4778. doi: 10.1007/s00210-024-03623-5. Epub 2024 Dec 5.
Chemotherapy (CT) is one of the flagship options for the treatment of cancers worldwide. It involves the use of cytotoxic anticancer agents to kill or inhibit the proliferation of cancer cells. However, despite its clinical efficacy, CT triggers side effect toxicities in several organs, which may impact cancer patient's quality of life and treatment outcomes. While the side effect toxicity is consistent with non-ferroptotic mechanisms involving oxidative stress, inflammation, mitochondrial impairment and other aberrant signalling leading to apoptosis and necroptosis, recent studies show that ferroptosis, a non-apoptotic, iron-dependent cell death pathway, is also involved in the pathophysiology of CT organ toxicity. CT provokes organ ferroptosis via system Xc/GPX-4/GSH/SLC7A11 axis depletion, ferritinophagy, iron overload, lipid peroxidation and upregulation of ferritin-related proteins. Cisplatin (CP) and doxorubicin (DOX) are common CT drugs indicated to induce ferroptosis in vitro and in vivo. Studies have explored natural preventive and therapeutic strategies using ginger rhizome and its major bioactive compounds, 6-gingerol (6G) and zingerone (ZG), to combat mechanisms of CT side effect toxicity. Ginger extract, 6G and ZG mitigate non-ferroptotic oxidative inflammation, apoptosis and mitochondrial dysfunction mechanisms of CT side effect toxicity, but their effects on CT-induced ferroptosis remain unclear. Systematic investigations are, therefore, needed to unfold the roles of ginger, 6G and ZG on ferroptosis involved in CT side effect toxicity, as they are potential natural agents for the prevention of CT toxicity. This review reveals the ferroptotic and non-ferroptotic toxicity mechanisms of CT and the protective mechanisms of ginger, 6G and ZG against CT-induced, ferroptotic and non-ferroptotic organ toxicities.
化疗（CT）是全球癌症治疗的主要手段之一。它涉及使用细胞毒性抗癌药物来杀死或抑制癌细胞的增殖。然而，尽管CT具有临床疗效，但它会在多个器官引发副作用毒性，这可能会影响癌症患者的生活质量和治疗效果。虽然副作用毒性与涉及氧化应激、炎症、线粒体损伤和其他导致凋亡和坏死性凋亡的异常信号传导的非铁死亡机制一致，但最近的研究表明，铁死亡是一种非凋亡性、铁依赖性细胞死亡途径，也参与了CT器官毒性的病理生理过程。CT通过系统Xc / GPX-4 / GSH / SLC7A11轴耗竭、铁蛋白自噬、铁过载、脂质过氧化和铁蛋白相关蛋白的上调引发器官铁死亡。顺铂（CP）和阿霉素（DOX）是常见的CT药物，已表明它们在体外和体内均可诱导铁死亡。研究探索了使用生姜根茎及其主要生物活性化合物6-姜酚（6G）和姜酮（ZG）来对抗CT副作用毒性机制的天然预防和治疗策略。生姜提取物、6G和ZG可减轻CT副作用毒性的非铁死亡性氧化炎症、凋亡和线粒体功能障碍机制，但其对CT诱导的铁死亡的影响仍不清楚。因此，需要进行系统研究以揭示生姜、6G和ZG在CT副作用毒性所涉及的铁死亡中的作用，因为它们是预防CT毒性的潜在天然药物。本综述揭示了CT的铁死亡和非铁死亡毒性机制以及生姜、6G和ZG对CT诱导的铁死亡和非铁死亡器官毒性的保护机制。
