Likitsatian Tanrada, Koonyosying Pimpisid, Paradee Narisara, Roytrakul Sittiruk, Ge Haobo, Pourzand Charareh, Srichairatanakool Somdet
Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.
National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency, Khlong Luang 12120, Thailand.
Nutrients. 2025 Feb 21;17(5):764. doi: 10.3390/nu17050764.
BACKGROUND/OBJECTIVE: Ferroptosis is an iron-dependent form of programmed cell death characterized by lipid peroxidation products (LPOs). A chemotherapeutic drug, 5-fluorouracil (5-FU), can induce epithelial mucositis and favor drug synergism with erastin in ferroptosis. tea saponin extract (TS) is known to exert antioxidative properties. This study aims to delineate the protective role of TS in mitigating 5-FU-induced ferroptosis and inflammation in human keratinocytes.
HaCaT cells were induced by 5-FU and erastin, treated with different TS doses, and their viability was then determined. Levels of cellular reactive oxygen species (ROS), LPOs, labile iron pool (LIP), glutathione (GSH), glutathione peroxidase 4 (GPX-4) activity, as well as IL-6, IL-1β, and TNF-α levels, and their wound healing properties were assessed.
TS per se (at up to 25 µg/mL) was not toxic to HaCaT cells but was unable to restore the viability of 5-FU-induced cells up to the baseline levels. The compound significantly diminished increases in cellular ROS, LPOs, and LIP, while restoring GSH content and GPX-4 activity. Additionally, it suppressed the cytokine production of 5-FU-induced cells in a concentration-dependent manner. Moreover, TS exerted wound-healing effects against skin injuries and 5-FU damage significantly and dose dependently.
The insights of this work have identified biochemical mechanisms using tea saponin extract to protect against 5-FU-induced keratinocyte ferroptosis and inflammation. This study highlights the promising adjunctive potential of tea saponin in the mitigation and management of chemotherapy-induced mucositis.
背景/目的：铁死亡是一种铁依赖性的程序性细胞死亡形式，其特征是脂质过氧化产物（LPOs）的产生。化疗药物5-氟尿嘧啶（5-FU）可诱发上皮性粘膜炎，并有利于与铁死亡诱导剂erastin产生药物协同作用。茶皂素提取物（TS）具有抗氧化特性。本研究旨在阐明TS在减轻5-FU诱导的人角质形成细胞铁死亡和炎症中的保护作用。
用5-FU和erastin诱导HaCaT细胞，并用不同剂量的TS处理，然后测定其活力。评估细胞活性氧（ROS）、LPOs、不稳定铁池（LIP）、谷胱甘肽（GSH）、谷胱甘肽过氧化物酶4（GPX-4）活性水平，以及白细胞介素-6（IL-6）、白细胞介素-1β（IL-1β）和肿瘤坏死因子-α（TNF-α）水平，及其伤口愈合特性。
TS本身（浓度高达25μg/mL）对HaCaT细胞无毒，但无法将5-FU诱导细胞的活力恢复到基线水平。该化合物显著减少了细胞ROS、LPOs和LIP的增加，同时恢复了GSH含量和GPX-4活性。此外，它以浓度依赖的方式抑制5-FU诱导细胞的细胞因子产生。此外，TS对皮肤损伤和5-FU损伤具有显著且剂量依赖性的伤口愈合作用。
本研究结果确定了茶皂素提取物预防5-FU诱导的角质形成细胞铁死亡和炎症的生化机制。本研究突出了茶皂素在减轻和管理化疗诱导的粘膜炎方面具有潜在的辅助应用前景。
