SIRT5-modified human umbilical cord mesenchymal stem cells loaded with antioxidant polydopamine nanozyme enhance parpi resistance in ovarian cancer via fatty acid metabolism reprogramming
Abstract Ovarian cancer remains one of the most aggressive cancers, and resistance to Poly (ADP-ribose) Polymerase inhibitors (PARPi) poses a major therapeutic challenge. SIRT5, a NAD + -dependent desuccinylase, plays a crucial role in regulating fatty acid metabolism, which is often reprogrammed in...
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BMC
2025-07-01
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| Series: | Journal of Nanobiotechnology |
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| Online Access: | https://doi.org/10.1186/s12951-025-03516-6 |
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| author | Jin Zhang Xiuluan Du Xin Dai Yanxiang Liu Kai Guo Donghua Gu |
| author_facet | Jin Zhang Xiuluan Du Xin Dai Yanxiang Liu Kai Guo Donghua Gu |
| author_sort | Jin Zhang |
| collection | DOAJ |
| description | Abstract Ovarian cancer remains one of the most aggressive cancers, and resistance to Poly (ADP-ribose) Polymerase inhibitors (PARPi) poses a major therapeutic challenge. SIRT5, a NAD + -dependent desuccinylase, plays a crucial role in regulating fatty acid metabolism, which is often reprogrammed in cancer cells to promote drug resistance. This study aimed to investigate the potential of polydopamine (PDA)-polymerized antioxidant nanozyme-loaded SIRT5-modified human umbilical cord mesenchymal stem cells (hUCMSCs) to overcome PARPi resistance in ovarian cancer. We employed multi-omics approaches, including transcriptomics, metabolomics, and proteomics, to identify key molecular pathways associated with resistance mechanisms. High-throughput sequencing and metabolic profiling revealed that SIRT5 modifies fatty acid β-oxidation and regulates the desuccinylation of Enoyl-CoA Hydratase (ECHA), a key enzyme involved in this process. In vitro and in vivo experiments demonstrated that nanozyme-engineered hUCMSCs effectively enhanced PARPi resistance by promoting fatty acid metabolism and desuccinylation. These findings suggest that SIRT5-modified hUCMSCs loaded with antioxidant nanozymes offer a promising therapeutic strategy to combat PARPi resistance in ovarian cancer. The study provides new insights into overcoming drug resistance through metabolic reprogramming and enhances the potential of engineered stem cells in cancer therapy. Graphical Abstract |
| format | Article |
| id | doaj-art-3a568c6822ce4e7da2ebe7f8d8b7d69d |
| institution | Kabale University |
| issn | 1477-3155 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Nanobiotechnology |
| spelling | doaj-art-3a568c6822ce4e7da2ebe7f8d8b7d69d2025-08-20T04:01:36ZengBMCJournal of Nanobiotechnology1477-31552025-07-0123112710.1186/s12951-025-03516-6SIRT5-modified human umbilical cord mesenchymal stem cells loaded with antioxidant polydopamine nanozyme enhance parpi resistance in ovarian cancer via fatty acid metabolism reprogrammingJin Zhang0Xiuluan Du1Xin Dai2Yanxiang Liu3Kai Guo4Donghua Gu5Department of Pathology, Suzhou Science & Technology Town HospitalDepartment of Pathology, Suzhou Science & Technology Town HospitalDepartment of Pathology, Suzhou Science & Technology Town HospitalDepartment of Pathology, Suzhou Science & Technology Town HospitalDepartment of Pathology, Suzhou Science & Technology Town HospitalDepartment of Pathology, Huzhou Central HospitalAbstract Ovarian cancer remains one of the most aggressive cancers, and resistance to Poly (ADP-ribose) Polymerase inhibitors (PARPi) poses a major therapeutic challenge. SIRT5, a NAD + -dependent desuccinylase, plays a crucial role in regulating fatty acid metabolism, which is often reprogrammed in cancer cells to promote drug resistance. This study aimed to investigate the potential of polydopamine (PDA)-polymerized antioxidant nanozyme-loaded SIRT5-modified human umbilical cord mesenchymal stem cells (hUCMSCs) to overcome PARPi resistance in ovarian cancer. We employed multi-omics approaches, including transcriptomics, metabolomics, and proteomics, to identify key molecular pathways associated with resistance mechanisms. High-throughput sequencing and metabolic profiling revealed that SIRT5 modifies fatty acid β-oxidation and regulates the desuccinylation of Enoyl-CoA Hydratase (ECHA), a key enzyme involved in this process. In vitro and in vivo experiments demonstrated that nanozyme-engineered hUCMSCs effectively enhanced PARPi resistance by promoting fatty acid metabolism and desuccinylation. These findings suggest that SIRT5-modified hUCMSCs loaded with antioxidant nanozymes offer a promising therapeutic strategy to combat PARPi resistance in ovarian cancer. The study provides new insights into overcoming drug resistance through metabolic reprogramming and enhances the potential of engineered stem cells in cancer therapy. Graphical Abstracthttps://doi.org/10.1186/s12951-025-03516-6Antioxidant nanozyme-engineered stem cellsMulti-omicsOvarian cancerPoly (ADP-ribose) polymerase inhibitors resistanceSIRT5Enoyl-CoA hydratase |
| spellingShingle | Jin Zhang Xiuluan Du Xin Dai Yanxiang Liu Kai Guo Donghua Gu SIRT5-modified human umbilical cord mesenchymal stem cells loaded with antioxidant polydopamine nanozyme enhance parpi resistance in ovarian cancer via fatty acid metabolism reprogramming Journal of Nanobiotechnology Antioxidant nanozyme-engineered stem cells Multi-omics Ovarian cancer Poly (ADP-ribose) polymerase inhibitors resistance SIRT5 Enoyl-CoA hydratase |
| title | SIRT5-modified human umbilical cord mesenchymal stem cells loaded with antioxidant polydopamine nanozyme enhance parpi resistance in ovarian cancer via fatty acid metabolism reprogramming |
| title_full | SIRT5-modified human umbilical cord mesenchymal stem cells loaded with antioxidant polydopamine nanozyme enhance parpi resistance in ovarian cancer via fatty acid metabolism reprogramming |
| title_fullStr | SIRT5-modified human umbilical cord mesenchymal stem cells loaded with antioxidant polydopamine nanozyme enhance parpi resistance in ovarian cancer via fatty acid metabolism reprogramming |
| title_full_unstemmed | SIRT5-modified human umbilical cord mesenchymal stem cells loaded with antioxidant polydopamine nanozyme enhance parpi resistance in ovarian cancer via fatty acid metabolism reprogramming |
| title_short | SIRT5-modified human umbilical cord mesenchymal stem cells loaded with antioxidant polydopamine nanozyme enhance parpi resistance in ovarian cancer via fatty acid metabolism reprogramming |
| title_sort | sirt5 modified human umbilical cord mesenchymal stem cells loaded with antioxidant polydopamine nanozyme enhance parpi resistance in ovarian cancer via fatty acid metabolism reprogramming |
| topic | Antioxidant nanozyme-engineered stem cells Multi-omics Ovarian cancer Poly (ADP-ribose) polymerase inhibitors resistance SIRT5 Enoyl-CoA hydratase |
| url | https://doi.org/10.1186/s12951-025-03516-6 |
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