Lenvatinib promotes hepatocellular carcinoma pyroptosis by regulating GSDME palmitoylation
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...
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Taylor & Francis Group
2025-12-01
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| Series: | Cancer Biology & Therapy |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/15384047.2025.2532217 |
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| author | Yuan Yuan Mu-Ru Wang Yang Ding Ya Lin Ting-Ting Xu Xing-Xing He Pei-Yuan Li |
| author_facet | Yuan Yuan Mu-Ru Wang Yang Ding Ya Lin Ting-Ting Xu Xing-Xing He Pei-Yuan Li |
| author_sort | Yuan Yuan |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-abf98ecccd8b4a57b0e2201d8105ede2 |
| institution | DOAJ |
| issn | 1538-4047 1555-8576 |
| language | English |
| publishDate | 2025-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Cancer Biology & Therapy |
| spelling | doaj-art-abf98ecccd8b4a57b0e2201d8105ede22025-08-20T03:11:42ZengTaylor & Francis GroupCancer Biology & Therapy1538-40471555-85762025-12-0126110.1080/15384047.2025.2532217Lenvatinib promotes hepatocellular carcinoma pyroptosis by regulating GSDME palmitoylationYuan Yuan0Mu-Ru Wang1Yang Ding2Ya Lin3Ting-Ting Xu4Xing-Xing He5Pei-Yuan Li6Division of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDivision of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, ChinaDivision of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDivision of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, ChinaDivision of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaLenvatinib, 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.https://www.tandfonline.com/doi/10.1080/15384047.2025.2532217Hepatocellular carcinomaLenvatinibpyroptosispalmitoylationGSDME |
| spellingShingle | Yuan Yuan Mu-Ru Wang Yang Ding Ya Lin Ting-Ting Xu Xing-Xing He Pei-Yuan Li Lenvatinib promotes hepatocellular carcinoma pyroptosis by regulating GSDME palmitoylation Cancer Biology & Therapy Hepatocellular carcinoma Lenvatinib pyroptosis palmitoylation GSDME |
| title | Lenvatinib promotes hepatocellular carcinoma pyroptosis by regulating GSDME palmitoylation |
| title_full | Lenvatinib promotes hepatocellular carcinoma pyroptosis by regulating GSDME palmitoylation |
| title_fullStr | Lenvatinib promotes hepatocellular carcinoma pyroptosis by regulating GSDME palmitoylation |
| title_full_unstemmed | Lenvatinib promotes hepatocellular carcinoma pyroptosis by regulating GSDME palmitoylation |
| title_short | Lenvatinib promotes hepatocellular carcinoma pyroptosis by regulating GSDME palmitoylation |
| title_sort | lenvatinib promotes hepatocellular carcinoma pyroptosis by regulating gsdme palmitoylation |
| topic | Hepatocellular carcinoma Lenvatinib pyroptosis palmitoylation GSDME |
| url | https://www.tandfonline.com/doi/10.1080/15384047.2025.2532217 |
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