托鲁巴茄 (Solanum torvum) (ST)用于清热毒、活血化瘀。因此，这种植物传统上被用作治疗普通感冒、慢性胃炎和肿瘤的民族药物。本研究旨在阐明 ST 诱导肝细胞癌 (HCC) 铁死亡的机制、与仑伐替尼的联合作用以及对使用 ST 处理的不同肝癌细胞系进行细胞活力测定。使用流式细胞术进行脂质过氧化和铁测定。通过蛋白质印迹法检测参与铁死亡途径的分子。最后，建立了乐伐替尼耐药细胞系，以评价ST的抗增殖作用。ST乙醇提取物可抑制多种肝癌细胞系的生长。 ST 处理后观察到谷胱甘肽过氧化物酶 4 (GPX4) 表达显着降低，同时脂质过氧化和 Fe2+ 积累增加。 ST主要通过血红素加氧酶-1（HO-1）表达诱导铁死亡。 HO-1 敲低可减少 ST 诱导的脂质过氧化并逆转 GPX4 抑制。酰基辅酶A合成酶长链家族成员4 (ACSL4)也参与ST诱导的铁死亡。 ST 和乐伐替尼组合显示出相加效应，并且 ST 在乐伐替尼耐药细胞系中保留了其潜在的抗 HCC 功效。本研究证明 ST 的乙醇提取物通过诱导铁死亡来抑制肝癌细胞生长。 ST 与 lenvatinib 在 Hep 3B 细胞中显示出相加效应，并且在 lenvatinib 耐药的 Hep 3B 细胞中显示出显着的抗 HCC 活性。总的来说，该研究表明 ST 可能有潜力减少临床实践中乐伐替尼的使用并挽救乐伐替尼耐药病例。版权所有 © 2024 Elsevier B.V. 保留所有权利。

Solanum torvum Sw. (ST) is used to clear heat toxins, promote blood circulation, and alleviate blood stasis. Therefore, this plant has traditionally been used as an ethnomedicine for common cold, chronic gastritis, and tumors.This study aimed to elucidate the mechanism by which ST induces ferroptosis in hepatocellular carcinoma (HCC), the combination effect with lenvatinib, and the impact on lenvatinib-resistant cells.Cell viability assays were performed using different hepatoma cell lines treated with ST. Lipid peroxidation and iron assays were performed using flow cytometry. Molecules involved in the ferroptosis pathway were detected by Western blotting. Finally, a lenvatinib-resistant cell line was established to evaluate the antiproliferative effects of ST.ST ethanol extract inhibited the growth of various hepatoma cell lines. A significant reduction in glutathione peroxidase 4 (GPX4) expression was observed following ST treatment, which was accompanied by increased lipid peroxidation and Fe2+ accumulation. ST induced ferroptosis mainly through heme oxygenase-1 (HO-1) expression. HO-1 knockdown reduced ST-induced lipid peroxidation and reversed GPX4 suppression. Acyl-CoA synthetase long-chain family member 4 (ACSL4) also participated in ST-induced ferroptosis. ST and lenvatinib combination showed an additive effect, and ST retained its potential anti-HCC efficacy in a lenvatinib-resistant cell line.This study demonstrated that the ethanol extract of ST inhibits hepatoma cell growth by inducing ferroptosis. ST displayed an additive effect with lenvatinib in Hep 3B cells and showed remarkable anti-HCC activity in lenvatinib-resistant Hep 3B cells. Collectively, the study shows that ST might have the potential to reduce lenvatinib use in clinical practice and salvage cases of lenvatinib resistance.Copyright © 2024 Elsevier B.V. All rights reserved.