CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Tiliroside induces ferroptosis and suppresses tumor growth by synergistically targeting AKR1B1 and modulating iron metabolism in ovarian cancer cells.
Tiliroside induces ferroptosis and suppresses tumor growth by synergistically targeting AKR1B1 and modulating iron metabolism in ovarian cancer cells.
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卵巢癌（OC）是常见恶性肿瘤，在妇科肿瘤中死亡率最高。Tiliroside（TIL）是一种具有多种药理活性的膳食糖苷类黄酮。本研究旨在探究 TIL 清除 OC 细胞的确切机制。方法与主要发现：体外实验中，TIL 通过诱导细胞死亡、抑制 A2780 和 OVCAR8 细胞侵袭和迁移发挥抗肿瘤作用。TIL 对 OC 细胞的抑制作用主要源于诱导铁死亡；证据是只有 ferrostatin-1（Fer-1）显著抑制 TIL 抗肿瘤活性，同时出现 ROS、MDA 和 Fe²⁺ 积累以及 GPX4 表达下降。SwissTargetPrediction、分子对接和 CETSA 试验显示，TIL 与 AKR1B1 直接相互作用会降低 AKR1B1 稳定性和表达。值得注意的是，AKR1B1 过表达显著减弱 TIL 对 OC 细胞增殖、侵袭、迁移和铁死亡的影响，但 Fe²⁺ 水平不变。RNA 测序结果提示，TIL 对铁稳态的调节可能与离子转运相关。Western 印迹和免疫荧光证实，TIL 可通过调节铁离子转运及铁蛋白自噬改变铁代谢，最终诱导铁死亡。在异种移植小鼠模型中，TIL 治疗可抑制肿瘤生长，且未造成明显组织损伤。
研究揭示 TIL 可同时靶向 AKR1B1 并调节铁代谢，从而诱导铁死亡、提高抗肿瘤疗效。作为一种新型药物，TIL 有望用于 OC 治疗。
AIMS: Ovarian cancer (OC) is a common malignant tumor with the greatest mortality rate among gynecological tumors. Tiliroside (TIL) is a glycosidic dietary flavonoid with various pharmacological activities. The purpose of this study was to investigate the exact mechanism by which TIL eliminates OC cells. METHODS/KEY FINDINGS: In vitro, TIL exerted anti-tumor activities by inducing cell death and inhibiting the invasion and migration of A2780 and OVCAR8 cells.
Additionally, the suppressive effect of TIL on OC cells was mainly due to the induction of ferroptosis, as demonstrated by the fact that only ferroprostatin-1 (Fer-1) significantly inhibited the anti-tumor activity of TIL, with the accumulation of ROS, MDA, and Fe 2+ and a reduction in GPX4 expression. SwissTargetPrediction, molecular docking and CETSA assay showed that the direct interaction between AKR1B1 and TIL decreased its stability and expression.
Notably, AKR1B1 overexpression significantly attenuated the effects of TIL on the proliferation, invasion, migration and ferroptosis on OC cells, whereas the levels of Fe 2+ remained unaffected. Interestingly, the results of the RNA sequencing (RNA-seq) analysis suggested that the regulation of iron homeostasis by TIL might be connected to ion transport.
Western blotting and immunofluorescence confirmed that TIL could modulate iron metabolism by regulating iron ion transport and ferritinophagy, ultimately resulting in ferroptosis. In xenograft model mice, TIL treatment inhibited tumor growth without causing substantial tissue damage. SIGNIFICANCE: Our research revealed that TIL simultaneously targets AKR1B1 and modulates iron metabolism, thereby inducing ferroptosis and improving anti-tumor efficacy. As a novel drug, TIL is promising for OC treatment.
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