PP1A Modulates the Efficacy of Lenvatinib Plus ICIs Therapy by Inhibiting Ferroptosis in Hepatocellular Carcinoma
Abstract Advanced hepatocellular carcinoma (HCC) is characterized by poor prognosis, primarily due to limited therapeutic options and resistance to treatment. Although the combination of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) has shown promising potential, the unde...
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Wiley
2025-07-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202501730 |
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| author | Jitong Zhou Meng Gao Shikun Zhang Wing‐Wa Guo Wenzhi He Minghe Zhang Xi Chen Cairang Dongzhi Xiaomian Li Yufeng Yuan Weijie Ma |
| author_facet | Jitong Zhou Meng Gao Shikun Zhang Wing‐Wa Guo Wenzhi He Minghe Zhang Xi Chen Cairang Dongzhi Xiaomian Li Yufeng Yuan Weijie Ma |
| author_sort | Jitong Zhou |
| collection | DOAJ |
| description | Abstract Advanced hepatocellular carcinoma (HCC) is characterized by poor prognosis, primarily due to limited therapeutic options and resistance to treatment. Although the combination of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) has shown promising potential, the underlying mechanisms remain inadequately understood. Here, serine/threonine‐specific protein phosphatase (PP1A) is upregulated in Lenvatinib‐resistant HCC cells and correlates with poor prognosis. Functional experiments revealed that PP1A promotes HCC progression both in vitro and in vivo. Transcriptomic analysis and ferroptosis metabolite profiling (e.g., ROS, Fe2⁺, lipid‐ROS, and GSH) demonstrated that PP1A inhibits Lenvatinib‐induced ferroptosis by dephosphorylating Keap1 at site 104. This disruption of the Keap1‐Nrf2 interaction enhances the transcription of ferroptosis‐related markers and immune checkpoint PD‐L1. Notably, single‐cell sequencing and co‐culture experiments revealed that PP1A knockdown alleviates T cell exhaustion and immune evasion, thereby improving antitumor immunity. In vivo experiments further demonstrated that PP1A knockdown significantly enhances the efficacy of Lenvatinib‐ICIs combination therapy. Overall, our findings highlight PP1A as a critical regulator of ferroptosis and antitumor immunity, suggesting its potential as a predictive biomarker and therapeutic target for improving outcomes in advanced HCC. |
| format | Article |
| id | doaj-art-b66faaabbca84663bedf5e6ca7e74d9d |
| institution | DOAJ |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-b66faaabbca84663bedf5e6ca7e74d9d2025-08-20T02:40:00ZengWileyAdvanced Science2198-38442025-07-011227n/an/a10.1002/advs.202501730PP1A Modulates the Efficacy of Lenvatinib Plus ICIs Therapy by Inhibiting Ferroptosis in Hepatocellular CarcinomaJitong Zhou0Meng Gao1Shikun Zhang2Wing‐Wa Guo3Wenzhi He4Minghe Zhang5Xi Chen6Cairang Dongzhi7Xiaomian Li8Yufeng Yuan9Weijie Ma10Department of Hepatobiliary and Pancreatic SurgeryZhongnan Hospital of Wuhan UniversityWuhan 430071 P. R. ChinaDepartment of Hepatobiliary and Pancreatic SurgeryZhongnan Hospital of Wuhan UniversityWuhan 430071 P. R. ChinaDepartment of Hepatobiliary and Pancreatic SurgeryZhongnan Hospital of Wuhan UniversityWuhan 430071 P. R. ChinaDepartment of Hepatobiliary and Pancreatic SurgeryZhongnan Hospital of Wuhan UniversityWuhan 430071 P. R. ChinaDepartment of Hepatobiliary and Pancreatic SurgeryZhongnan Hospital of Wuhan UniversityWuhan 430071 P. R. ChinaDepartment of Hepatobiliary and Pancreatic SurgeryZhongnan Hospital of Wuhan UniversityWuhan 430071 P. R. ChinaDepartment of Hepatobiliary and Pancreatic SurgeryZhongnan Hospital of Wuhan UniversityWuhan 430071 P. R. ChinaDepartment of Hepatobiliary and Pancreatic SurgeryZhongnan Hospital of Wuhan UniversityWuhan 430071 P. R. ChinaDepartment of Hepatobiliary and Pancreatic SurgeryZhongnan Hospital of Wuhan UniversityWuhan 430071 P. R. ChinaDepartment of Hepatobiliary and Pancreatic SurgeryZhongnan Hospital of Wuhan UniversityWuhan 430071 P. R. ChinaDepartment of Hepatobiliary and Pancreatic SurgeryZhongnan Hospital of Wuhan UniversityWuhan 430071 P. R. ChinaAbstract Advanced hepatocellular carcinoma (HCC) is characterized by poor prognosis, primarily due to limited therapeutic options and resistance to treatment. Although the combination of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) has shown promising potential, the underlying mechanisms remain inadequately understood. Here, serine/threonine‐specific protein phosphatase (PP1A) is upregulated in Lenvatinib‐resistant HCC cells and correlates with poor prognosis. Functional experiments revealed that PP1A promotes HCC progression both in vitro and in vivo. Transcriptomic analysis and ferroptosis metabolite profiling (e.g., ROS, Fe2⁺, lipid‐ROS, and GSH) demonstrated that PP1A inhibits Lenvatinib‐induced ferroptosis by dephosphorylating Keap1 at site 104. This disruption of the Keap1‐Nrf2 interaction enhances the transcription of ferroptosis‐related markers and immune checkpoint PD‐L1. Notably, single‐cell sequencing and co‐culture experiments revealed that PP1A knockdown alleviates T cell exhaustion and immune evasion, thereby improving antitumor immunity. In vivo experiments further demonstrated that PP1A knockdown significantly enhances the efficacy of Lenvatinib‐ICIs combination therapy. Overall, our findings highlight PP1A as a critical regulator of ferroptosis and antitumor immunity, suggesting its potential as a predictive biomarker and therapeutic target for improving outcomes in advanced HCC.https://doi.org/10.1002/advs.202501730combination therapyferroptosisimmune checkpoint inhibitorslenvatinibPD‐L1PP1A |
| spellingShingle | Jitong Zhou Meng Gao Shikun Zhang Wing‐Wa Guo Wenzhi He Minghe Zhang Xi Chen Cairang Dongzhi Xiaomian Li Yufeng Yuan Weijie Ma PP1A Modulates the Efficacy of Lenvatinib Plus ICIs Therapy by Inhibiting Ferroptosis in Hepatocellular Carcinoma Advanced Science combination therapy ferroptosis immune checkpoint inhibitors lenvatinib PD‐L1 PP1A |
| title | PP1A Modulates the Efficacy of Lenvatinib Plus ICIs Therapy by Inhibiting Ferroptosis in Hepatocellular Carcinoma |
| title_full | PP1A Modulates the Efficacy of Lenvatinib Plus ICIs Therapy by Inhibiting Ferroptosis in Hepatocellular Carcinoma |
| title_fullStr | PP1A Modulates the Efficacy of Lenvatinib Plus ICIs Therapy by Inhibiting Ferroptosis in Hepatocellular Carcinoma |
| title_full_unstemmed | PP1A Modulates the Efficacy of Lenvatinib Plus ICIs Therapy by Inhibiting Ferroptosis in Hepatocellular Carcinoma |
| title_short | PP1A Modulates the Efficacy of Lenvatinib Plus ICIs Therapy by Inhibiting Ferroptosis in Hepatocellular Carcinoma |
| title_sort | pp1a modulates the efficacy of lenvatinib plus icis therapy by inhibiting ferroptosis in hepatocellular carcinoma |
| topic | combination therapy ferroptosis immune checkpoint inhibitors lenvatinib PD‐L1 PP1A |
| url | https://doi.org/10.1002/advs.202501730 |
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