Matrix stiffness regulates glucose-6-phosphate dehydrogenase expression to mediate sorafenib resistance in hepatocellular carcinoma through the ITGB1-PI3K/AKT pathway
Abstract Sorafenib is an antiangiogenic and antiproliferative chemotherapeutic drug that plays a crucial role in the treatment of patients with advanced hepatocellular carcinoma (HCC). However, resistance to sorafenib greatly limits its therapeutic efficacy. This highlights the importance of determi...
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| Format: | Article |
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Nature Publishing Group
2025-07-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07842-3 |
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| author | Ruimei Ren Shan Zhang Zhan Peng Xiaomeng Ji Hao Song Qiuxiao Wang Xiangyin Sun Huiyu Wang Yinying Dong |
| author_facet | Ruimei Ren Shan Zhang Zhan Peng Xiaomeng Ji Hao Song Qiuxiao Wang Xiangyin Sun Huiyu Wang Yinying Dong |
| author_sort | Ruimei Ren |
| collection | DOAJ |
| description | Abstract Sorafenib is an antiangiogenic and antiproliferative chemotherapeutic drug that plays a crucial role in the treatment of patients with advanced hepatocellular carcinoma (HCC). However, resistance to sorafenib greatly limits its therapeutic efficacy. This highlights the importance of determining the mechanisms underlying resistance to antiangiogenic therapy. In this study, we found that the extracellular matrix (ECM) stiffness was closely related to the prognosis of HCC patients and chemotherapy resistance. Using atomic force microscopy, we assessed ECM stiffness in tumor samples from 30 HCC patients treated with sorafenib, and the ECM stiffness in sorafenib-resistant patients was significantly greater than that in those who responded to sorafenib treatment. In a liver orthotopic xenograft model, reducing tumor ECM stiffness by inhibiting LOX enzyme activity significantly enhanced the efficacy of sorafenib and suppressed tumor progression. We found that glucose-6-phosphate dehydrogenase (G6PD) is regulated by ECM stiffness and is involved in resistance to sorafenib. Further in vitro and in vivo experiments confirmed that ECM stiffness can upregulate G6PD expression through the ITGB1-PI3K/AKT pathway, mediating sorafenib resistance in HCC. Clinical tissue microarray analysis revealed that the expression of collagen I, α-SMA, ITGB1, p-AKT, and G6PD was associated with sorafenib resistance in HCC patients. These results indicated that reducing ECM stiffness can increase the sensitivity of HCC to sorafenib and that the ITGB1-PI3K/AKT-G6PD cascades may serve as potential therapeutic targets for reversing sorafenib resistance. |
| format | Article |
| id | doaj-art-a8bf30c1841e46669a3379346c2a47c4 |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-a8bf30c1841e46669a3379346c2a47c42025-08-20T03:42:10ZengNature Publishing GroupCell Death and Disease2041-48892025-07-0116111210.1038/s41419-025-07842-3Matrix stiffness regulates glucose-6-phosphate dehydrogenase expression to mediate sorafenib resistance in hepatocellular carcinoma through the ITGB1-PI3K/AKT pathwayRuimei Ren0Shan Zhang1Zhan Peng2Xiaomeng Ji3Hao Song4Qiuxiao Wang5Xiangyin Sun6Huiyu Wang7Yinying Dong8Department of Radiation Oncology, The Affiliated Hospital of Qingdao UniversityState Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong UniversityDepartment of Radiation Oncology, The Affiliated Hospital of Qingdao UniversityDepartment of Radiation Oncology, The Affiliated Hospital of Qingdao UniversityDepartment of Radiation Oncology, The Affiliated Hospital of Qingdao UniversityDepartment of Radiation Oncology, The Affiliated Hospital of Qingdao UniversityDepartment of Oncology, Qingdao Sixth People’s HospitalDepartment of Radiation Oncology, Qingdao Chengyang District People’s HospitalDepartment of Radiation Oncology, The Affiliated Hospital of Qingdao UniversityAbstract Sorafenib is an antiangiogenic and antiproliferative chemotherapeutic drug that plays a crucial role in the treatment of patients with advanced hepatocellular carcinoma (HCC). However, resistance to sorafenib greatly limits its therapeutic efficacy. This highlights the importance of determining the mechanisms underlying resistance to antiangiogenic therapy. In this study, we found that the extracellular matrix (ECM) stiffness was closely related to the prognosis of HCC patients and chemotherapy resistance. Using atomic force microscopy, we assessed ECM stiffness in tumor samples from 30 HCC patients treated with sorafenib, and the ECM stiffness in sorafenib-resistant patients was significantly greater than that in those who responded to sorafenib treatment. In a liver orthotopic xenograft model, reducing tumor ECM stiffness by inhibiting LOX enzyme activity significantly enhanced the efficacy of sorafenib and suppressed tumor progression. We found that glucose-6-phosphate dehydrogenase (G6PD) is regulated by ECM stiffness and is involved in resistance to sorafenib. Further in vitro and in vivo experiments confirmed that ECM stiffness can upregulate G6PD expression through the ITGB1-PI3K/AKT pathway, mediating sorafenib resistance in HCC. Clinical tissue microarray analysis revealed that the expression of collagen I, α-SMA, ITGB1, p-AKT, and G6PD was associated with sorafenib resistance in HCC patients. These results indicated that reducing ECM stiffness can increase the sensitivity of HCC to sorafenib and that the ITGB1-PI3K/AKT-G6PD cascades may serve as potential therapeutic targets for reversing sorafenib resistance.https://doi.org/10.1038/s41419-025-07842-3 |
| spellingShingle | Ruimei Ren Shan Zhang Zhan Peng Xiaomeng Ji Hao Song Qiuxiao Wang Xiangyin Sun Huiyu Wang Yinying Dong Matrix stiffness regulates glucose-6-phosphate dehydrogenase expression to mediate sorafenib resistance in hepatocellular carcinoma through the ITGB1-PI3K/AKT pathway Cell Death and Disease |
| title | Matrix stiffness regulates glucose-6-phosphate dehydrogenase expression to mediate sorafenib resistance in hepatocellular carcinoma through the ITGB1-PI3K/AKT pathway |
| title_full | Matrix stiffness regulates glucose-6-phosphate dehydrogenase expression to mediate sorafenib resistance in hepatocellular carcinoma through the ITGB1-PI3K/AKT pathway |
| title_fullStr | Matrix stiffness regulates glucose-6-phosphate dehydrogenase expression to mediate sorafenib resistance in hepatocellular carcinoma through the ITGB1-PI3K/AKT pathway |
| title_full_unstemmed | Matrix stiffness regulates glucose-6-phosphate dehydrogenase expression to mediate sorafenib resistance in hepatocellular carcinoma through the ITGB1-PI3K/AKT pathway |
| title_short | Matrix stiffness regulates glucose-6-phosphate dehydrogenase expression to mediate sorafenib resistance in hepatocellular carcinoma through the ITGB1-PI3K/AKT pathway |
| title_sort | matrix stiffness regulates glucose 6 phosphate dehydrogenase expression to mediate sorafenib resistance in hepatocellular carcinoma through the itgb1 pi3k akt pathway |
| url | https://doi.org/10.1038/s41419-025-07842-3 |
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