Yuan Yuan, Wang Mu-Ru, Ding Yang, Lin Ya, Xu Ting-Ting, He Xing-Xing, Li Pei-Yuan
Division of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.
Cancer Biol Ther. 2025 Dec;26(1):2532217. doi: 10.1080/15384047.2025.2532217. Epub 2025 Jul 13.
Lenvatinib, as a multi-kinase inhibitor, has been approved as a first-line drug for patients with advanced hepatocellular carcinoma (HCC). Gasdermin E (GSDME)-mediated pyroptosis, a form of programmed cell death, can be induced by chemotherapy drugs or certain kinase inhibitors. However, the role of Lenvatinib in inducing pyroptosis in HCC warrants further investigation. Phase contrast microscopy, LDH assays, and gain- and loss-of-function strategies were used to evaluate Lenvatinib-induced pyroptosis in HCC cells. GSDME palmitoylation was assessed via the acyl-biotin exchange method. In vivo, a subcutaneous HCC xenograft model in nude mice were established to assess the effects of interfering with GSDME on the sensitivity of HCC to Lenvatinib. Lenvatinib induced pyroptosis in HCC cells in a dose- and time-dependent manner. Additionally, Lenvatinib promoted GSDME cleavage, with upregulation of GSDME enhancing pyroptosis and downregulation reducing this effect. The ABE method revealed that GSDME is palmitoylated, and Lenvatinib increased its palmitoylation, promoting plasma membrane localization and enhancing protein stability. Inhibition of GSDME palmitoylation by 2-BP blocked Lenvatinib-induced pyroptosis. In vivo, upregulation of GSDME increased HCC sensitivity to Lenvatinib and inhibited tumor growth. Lenvatinib induces pyroptosis in HCC by promoting the palmitoylation of GSDME, enhancing its localization to the plasma membrane and increasing its protein stability. Interfering with GSDME, both in vitro and in vivo, affects Lenvatinib-induced pyroptosis, thereby altering the therapeutic sensitivity of HCC to Lenvatinib. Targeting GSDME palmitoylation represents a potential therapeutic strategy for HCC, as it enhances Lenvatinib-induced pyroptosis and improves the therapeutic response.
乐伐替尼作为一种多激酶抑制剂，已被批准作为晚期肝细胞癌（HCC）患者的一线用药。Gasdermin E（GSDME）介导的细胞焦亡是一种程序性细胞死亡形式，可由化疗药物或某些激酶抑制剂诱导。然而，乐伐替尼在诱导肝癌细胞焦亡中的作用值得进一步研究。采用相差显微镜、乳酸脱氢酶（LDH）检测以及功能获得和功能缺失策略来评估乐伐替尼诱导肝癌细胞焦亡的情况。通过酰基生物素交换法评估GSDME的棕榈酰化。在体内，建立了裸鼠皮下肝癌异种移植模型，以评估干扰GSDME对肝癌对乐伐替尼敏感性的影响。乐伐替尼以剂量和时间依赖性方式诱导肝癌细胞焦亡。此外，乐伐替尼促进GSDME的切割，GSDME的上调增强细胞焦亡，而下调则降低这种作用。ABE方法显示GSDME被棕榈酰化，乐伐替尼增加其棕榈酰化，促进质膜定位并增强蛋白质稳定性。2 - BP抑制GSDME棕榈酰化可阻断乐伐替尼诱导的细胞焦亡。在体内，GSDME的上调增加了肝癌对乐伐替尼的敏感性并抑制肿瘤生长。乐伐替尼通过促进GSDME的棕榈酰化、增强其在质膜上的定位并增加其蛋白质稳定性来诱导肝癌细胞焦亡。在体外和体内干扰GSDME都会影响乐伐替尼诱导的细胞焦亡，从而改变肝癌对乐伐替尼的治疗敏感性。靶向GSDME棕榈酰化代表了一种潜在的肝癌治疗策略，因为它增强了乐伐替尼诱导的细胞焦亡并改善了治疗反应。
