FLNA, a disulfidptosis-related gene, modulates tumor immunity and progression in colorectal cancer
Abstract Background Disulfidptosis represents a novel type of regulated cell death induced by excessively high intracellular levels of cystine. Targeting disulfide imbalance is considered a promising treatment approach for colorectal cancer (CRC). However, the involvement of disulfidptosis in CRC im...
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BMC
2025-07-01
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| Series: | Cellular & Molecular Biology Letters |
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| Online Access: | https://doi.org/10.1186/s11658-025-00761-3 |
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| author | Qiong Li Renhong Huang Lingling Lv Haifeng Ying Yuan Wu YuQing Huang Yuxi Li Wen Ma Xiaoshuang Liu Qinghui Meng Fengying Xing Yan Shen Lan Zheng |
| author_facet | Qiong Li Renhong Huang Lingling Lv Haifeng Ying Yuan Wu YuQing Huang Yuxi Li Wen Ma Xiaoshuang Liu Qinghui Meng Fengying Xing Yan Shen Lan Zheng |
| author_sort | Qiong Li |
| collection | DOAJ |
| description | Abstract Background Disulfidptosis represents a novel type of regulated cell death induced by excessively high intracellular levels of cystine. Targeting disulfide imbalance is considered a promising treatment approach for colorectal cancer (CRC). However, the involvement of disulfidptosis in CRC immunotherapy is undefined. Methods Unsupervised clustering was applied to The Cancer Genome Atlas (TCGA) datasets to classify disulfidptosis-related phenotypes. The tumor microenvironment (TME) was characterized using diverse bioinformatics algorithms, including gene set variation analysis (GSVA) for pathway enrichment analysis and CIBERSORT for immune cell profiling. A disulfidptosis-related gene (DRG) signature was generated for stratifying CRC cases, and univariate Cox regression was utilized for identifying prognostic DRGs. Filamin A (FLNA) was pinpointed as a pivotal regulator of disulfidptosis, and its functional impacts on tumor progression and immunotherapy response were further investigated. Results Two different groups were determined on the basis of the built disulfidptosis-related signature (DRS), showing distinct clinical outcomes, as well as different pathway activation, drug sensitivity, and immune infiltration patterns. The high-DRS subgroup correlated with poorer prognosis, elevated immunosuppressive cell activity, and reduced cytotoxic immune cell infiltration. FLNA emerged as a critical mediator of disulfidptosis in CRC, with its knockdown suppressing tumor cell migration and invasion in vitro. The FLNA inhibitor PTI-125 attenuated tumor growth and epithelial–mesenchymal transition (EMT), while FLNA depletion reversed glucose-driven metastasis. Notably, combined glucose transporter 1 (GLUT1) inhibition and anti-programmed cell death protein 1 (PD-1) therapy enhanced CD8+ T cell recruitment and suppressed EMT. Conclusions This study elucidates the interplay between disulfidptosis and the CRC immune landscape, highlighting FLNA as a therapeutic target. These findings suggest that modulating disulfidptosis in conjunction with immunotherapy may offer a novel treatment paradigm for CRC. |
| format | Article |
| id | doaj-art-07ec531d47a94ff8b9ecdb92dabc50a0 |
| institution | Kabale University |
| issn | 1689-1392 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Cellular & Molecular Biology Letters |
| spelling | doaj-art-07ec531d47a94ff8b9ecdb92dabc50a02025-08-20T04:03:02ZengBMCCellular & Molecular Biology Letters1689-13922025-07-0130112210.1186/s11658-025-00761-3FLNA, a disulfidptosis-related gene, modulates tumor immunity and progression in colorectal cancerQiong Li0Renhong Huang1Lingling Lv2Haifeng Ying3Yuan Wu4YuQing Huang5Yuxi Li6Wen Ma7Xiaoshuang Liu8Qinghui Meng9Fengying Xing10Yan Shen11Lan Zheng12Shuguang Hospital, Shanghai University of Traditional Chinese MedicineDepartment of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Traditional Chinese Medicine, Ruijin Hospital, Shanghai Jiaotong University School of MedicineDepartment of Traditional Chinese Medicine, Ruijin Hospital, Shanghai Jiaotong University School of MedicineDepartment of Traditional Chinese Medicine, Ruijin Hospital, Shanghai Jiaotong University School of MedicineDepartment of Traditional Chinese Medicine, Ruijin Hospital, Shanghai Jiaotong University School of MedicineDepartment of Traditional Chinese Medicine, Ruijin Hospital, Shanghai Jiaotong University School of MedicineDepartment of Acupuncture, Shuguang Hospital, Shanghai University of Traditional Chinese MedicineDepartment of General Surgery, Shuguang Hospital, Shanghai University of Traditional Chinese MedicineBeijing Research Institute of Science and Technology, Beijing Milu Ecological Research CenterExperimental Animal Center, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of MedicineState Key Laboratory of Medical Genomics, Research Center for Experimental Medicine, Ruijin Hospital, Shanghai Jiaotong University School of MedicineDepartment of Acupuncture, Shuguang Hospital, Shanghai University of Traditional Chinese MedicineAbstract Background Disulfidptosis represents a novel type of regulated cell death induced by excessively high intracellular levels of cystine. Targeting disulfide imbalance is considered a promising treatment approach for colorectal cancer (CRC). However, the involvement of disulfidptosis in CRC immunotherapy is undefined. Methods Unsupervised clustering was applied to The Cancer Genome Atlas (TCGA) datasets to classify disulfidptosis-related phenotypes. The tumor microenvironment (TME) was characterized using diverse bioinformatics algorithms, including gene set variation analysis (GSVA) for pathway enrichment analysis and CIBERSORT for immune cell profiling. A disulfidptosis-related gene (DRG) signature was generated for stratifying CRC cases, and univariate Cox regression was utilized for identifying prognostic DRGs. Filamin A (FLNA) was pinpointed as a pivotal regulator of disulfidptosis, and its functional impacts on tumor progression and immunotherapy response were further investigated. Results Two different groups were determined on the basis of the built disulfidptosis-related signature (DRS), showing distinct clinical outcomes, as well as different pathway activation, drug sensitivity, and immune infiltration patterns. The high-DRS subgroup correlated with poorer prognosis, elevated immunosuppressive cell activity, and reduced cytotoxic immune cell infiltration. FLNA emerged as a critical mediator of disulfidptosis in CRC, with its knockdown suppressing tumor cell migration and invasion in vitro. The FLNA inhibitor PTI-125 attenuated tumor growth and epithelial–mesenchymal transition (EMT), while FLNA depletion reversed glucose-driven metastasis. Notably, combined glucose transporter 1 (GLUT1) inhibition and anti-programmed cell death protein 1 (PD-1) therapy enhanced CD8+ T cell recruitment and suppressed EMT. Conclusions This study elucidates the interplay between disulfidptosis and the CRC immune landscape, highlighting FLNA as a therapeutic target. These findings suggest that modulating disulfidptosis in conjunction with immunotherapy may offer a novel treatment paradigm for CRC.https://doi.org/10.1186/s11658-025-00761-3DisulfidptosisFilamin AEpithelial mesenchymal transitionGlucose transporter 1ImmunotherapyColorectal cancer |
| spellingShingle | Qiong Li Renhong Huang Lingling Lv Haifeng Ying Yuan Wu YuQing Huang Yuxi Li Wen Ma Xiaoshuang Liu Qinghui Meng Fengying Xing Yan Shen Lan Zheng FLNA, a disulfidptosis-related gene, modulates tumor immunity and progression in colorectal cancer Cellular & Molecular Biology Letters Disulfidptosis Filamin A Epithelial mesenchymal transition Glucose transporter 1 Immunotherapy Colorectal cancer |
| title | FLNA, a disulfidptosis-related gene, modulates tumor immunity and progression in colorectal cancer |
| title_full | FLNA, a disulfidptosis-related gene, modulates tumor immunity and progression in colorectal cancer |
| title_fullStr | FLNA, a disulfidptosis-related gene, modulates tumor immunity and progression in colorectal cancer |
| title_full_unstemmed | FLNA, a disulfidptosis-related gene, modulates tumor immunity and progression in colorectal cancer |
| title_short | FLNA, a disulfidptosis-related gene, modulates tumor immunity and progression in colorectal cancer |
| title_sort | flna a disulfidptosis related gene modulates tumor immunity and progression in colorectal cancer |
| topic | Disulfidptosis Filamin A Epithelial mesenchymal transition Glucose transporter 1 Immunotherapy Colorectal cancer |
| url | https://doi.org/10.1186/s11658-025-00761-3 |
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