Hepatocellular carcinoma (HCC) remains one of the most common cancers worldwide. Asiatic acid (AA) is a natural triterpene, which is recognized as effect of antioxidant and antitumor. Sorafenib (Sor), an orally target drug, has been applicate for the HCC therapy. However, the synergistic effect of AA and Sor on human HCC is still unclear. Here, we explore the effect of combined treatment with AA and Sor in the HCC cell line SK‐HEP‐1 and HepG2. Compared with treating alone, our results demonstrated that AA combined with Sor synergistically inhibited proliferative rates in MTT assay and colony formation assay. We also found that AA combined with Sor in HCC cells strongly caused cell cycle arrest in G0/G1 phase and affected the protein level of cyclin D1 and SKP2. Furthermore, combination treatment strongly enhanced ferroptosis through cellular accumulation of iron ions, lipid peroxidation, and ferroptosis‐related proteins (GPX4 and FTH1) in HCC cells. In addition, the combined treatment resulted in higher phosphorylation of JNK1/2 in the promotion of ferroptosis than drug treatment alone. These results indicate that AA combined with Sor synergistically improved ferroptosis in HCC cells through the regulation of JNK1/2 signaling. Taken together, the combinatorial strategy may serve as the potential treatment in HCC.

中文翻译：

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索拉非尼是一种酪氨酸激酶抑制剂，协同增强巷壁酸在肝细胞癌细胞中的铁死亡作用


肝细胞癌 （HCC） 仍然是全球最常见的癌症之一。积雪草酸 （AA） 是一种天然三萜，被认为是抗氧化和抗肿瘤的作用。索拉非尼 （Sor） 是一种口服靶向药物，已应用于 HCC 治疗。然而，AA 和 Sor 对人类 HCC 的协同作用仍不清楚。在这里，我们探讨了 AA 和 Sor 联合治疗对 HCC 细胞系 SK-HEP-1 和 HepG2 的影响。与单独治疗相比，我们的结果表明，AA 联合 Sor 协同抑制 MTT 测定和集落形成测定中的增殖率。我们还发现 AA 与 Sor 在 HCC 细胞中强烈导致细胞周期停滞在 G0/G1 期，并影响细胞周期蛋白 D1 和 SKP2 的蛋白水平。此外，联合治疗通过 HCC 细胞中铁离子、脂质过氧化和铁死亡相关蛋白 （GPX4 和 FTH1） 的细胞积累强烈增强了铁死亡。此外，与单独药物治疗相比，联合治疗在促进铁死亡方面导致更高的 JNK1/2 磷酸化。这些结果表明，AA 与 Sor 结合通过调节 JNK1/2 信号传导协同改善 HCC 细胞的铁死亡。综上所述，组合策略可能作为 HCC 的潜在治疗方法。