A dual inhibitor of TrxR1 and XIAP induces pyroptosis in melanoma
Malignant melanoma ranks among the most aggressive forms of cancer, with high rates of metastasis and recurrence, as well as a poor prognosis. Consequently, an urgent need is to develop novel precision therapeutic strategies and corresponding drugs. Previous studies have shown that both X-linked inh...
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| Format: | Article |
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Frontiers Media S.A.
2025-05-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2025.1542356/full |
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| author | Yuan Wang Yuan Wang Xiangmei Li Xinyue Dong Haokun Yuan Ruiqin Fang Ran Zhang Wei-jia Wang Wei-jia Wang |
| author_facet | Yuan Wang Yuan Wang Xiangmei Li Xinyue Dong Haokun Yuan Ruiqin Fang Ran Zhang Wei-jia Wang Wei-jia Wang |
| author_sort | Yuan Wang |
| collection | DOAJ |
| description | Malignant melanoma ranks among the most aggressive forms of cancer, with high rates of metastasis and recurrence, as well as a poor prognosis. Consequently, an urgent need is to develop novel precision therapeutic strategies and corresponding drugs. Previous studies have shown that both X-linked inhibitor of apoptosis (XIAP) and thioredoxin reductase 1 (TrxR1) participate in the resistance of melanoma to chemotherapy-induced cell death. In this study, we designed and synthesized a series of derivatives of natural compounds derived from Toona sinensis to simultaneously inhibit TrxR1 activity and destabilize the XIAP protein. The new dual-target inhibitor TRI-03 has significant antiproliferative effects on melanoma cells. Mechanistically, TRI-03 not only increases intracellular reactive oxygen species (ROS) levels by inhibiting TrxR1 activity but also decreases XIAP expression, leading to the activation of the caspase-9/caspase-3/GSDME axis and irreversible GSDME-mediated pyroptosis in melanoma cells. Our in vivo animal study confirmed that TRI-03 effectively inhibits melanoma proliferation and metastasis without severe side effects. Therefore, our study identified TRI-03 as a potential antitumor candidate for future development to address melanoma. |
| format | Article |
| id | doaj-art-fb388df11e4040d6aa0a409b6e6b6456 |
| institution | DOAJ |
| issn | 2296-634X |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj-art-fb388df11e4040d6aa0a409b6e6b64562025-08-20T03:13:30ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2025-05-011310.3389/fcell.2025.15423561542356A dual inhibitor of TrxR1 and XIAP induces pyroptosis in melanomaYuan Wang0Yuan Wang1Xiangmei Li2Xinyue Dong3Haokun Yuan4Ruiqin Fang5Ran Zhang6Wei-jia Wang7Wei-jia Wang8The School of Medicine, University of Electronic Science and Technology of China, Chengdu, ChinaThe Key Laboratory for Human Disease Gene Study of Sichuan Province and the Department of Laboratory Medicine, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, ChinaThe School of Medicine, University of Electronic Science and Technology of China, Chengdu, ChinaThe School of Medicine, University of Electronic Science and Technology of China, Chengdu, ChinaDivision of Neonatology, Department of Pediatrics, The Affiliated Hospital of Southwest Medical University, Luzhou, ChinaThe School of Life Science, University of Electronic Science and Technology of China, Chengdu, ChinaFaculty of Science and Engineering, University of Groningen, Groningen, NetherlandsFujian Provincial Key Laboratory of Translational Cancer Medicine, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, ChinaState Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, ChinaMalignant melanoma ranks among the most aggressive forms of cancer, with high rates of metastasis and recurrence, as well as a poor prognosis. Consequently, an urgent need is to develop novel precision therapeutic strategies and corresponding drugs. Previous studies have shown that both X-linked inhibitor of apoptosis (XIAP) and thioredoxin reductase 1 (TrxR1) participate in the resistance of melanoma to chemotherapy-induced cell death. In this study, we designed and synthesized a series of derivatives of natural compounds derived from Toona sinensis to simultaneously inhibit TrxR1 activity and destabilize the XIAP protein. The new dual-target inhibitor TRI-03 has significant antiproliferative effects on melanoma cells. Mechanistically, TRI-03 not only increases intracellular reactive oxygen species (ROS) levels by inhibiting TrxR1 activity but also decreases XIAP expression, leading to the activation of the caspase-9/caspase-3/GSDME axis and irreversible GSDME-mediated pyroptosis in melanoma cells. Our in vivo animal study confirmed that TRI-03 effectively inhibits melanoma proliferation and metastasis without severe side effects. Therefore, our study identified TRI-03 as a potential antitumor candidate for future development to address melanoma.https://www.frontiersin.org/articles/10.3389/fcell.2025.1542356/fullmelanomapyroptosisthioredoxin reductase 1 (TrxR1)X-linked inhibitor of apoptosis (XIAP)reactive oxygen species |
| spellingShingle | Yuan Wang Yuan Wang Xiangmei Li Xinyue Dong Haokun Yuan Ruiqin Fang Ran Zhang Wei-jia Wang Wei-jia Wang A dual inhibitor of TrxR1 and XIAP induces pyroptosis in melanoma Frontiers in Cell and Developmental Biology melanoma pyroptosis thioredoxin reductase 1 (TrxR1) X-linked inhibitor of apoptosis (XIAP) reactive oxygen species |
| title | A dual inhibitor of TrxR1 and XIAP induces pyroptosis in melanoma |
| title_full | A dual inhibitor of TrxR1 and XIAP induces pyroptosis in melanoma |
| title_fullStr | A dual inhibitor of TrxR1 and XIAP induces pyroptosis in melanoma |
| title_full_unstemmed | A dual inhibitor of TrxR1 and XIAP induces pyroptosis in melanoma |
| title_short | A dual inhibitor of TrxR1 and XIAP induces pyroptosis in melanoma |
| title_sort | dual inhibitor of trxr1 and xiap induces pyroptosis in melanoma |
| topic | melanoma pyroptosis thioredoxin reductase 1 (TrxR1) X-linked inhibitor of apoptosis (XIAP) reactive oxygen species |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2025.1542356/full |
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