The EZH2 selective inhibitor ZLD1039 attenuates UUO-induced renal fibrosis by suppressing YAP activation
Abstract Renal fibrosis is a manifestation of the progression of chronic kidney disease (CKD) and chronic inflammation is a main driver in the development of renal fibrosis. Yes-associated protein (YAP), acting as a transcriptional co-activator within the Hippo signaling pathway, has been implicated...
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Springer
2025-06-01
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| Series: | Molecular Biomedicine |
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| Online Access: | https://doi.org/10.1186/s43556-025-00276-5 |
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| author | Qingling Xia Fujiang Xu Lidan Zhang Wenfei Ding Jiang Liu Jing Liu Minhao Chen Santao Ou Yong Xu Li Wen |
| author_facet | Qingling Xia Fujiang Xu Lidan Zhang Wenfei Ding Jiang Liu Jing Liu Minhao Chen Santao Ou Yong Xu Li Wen |
| author_sort | Qingling Xia |
| collection | DOAJ |
| description | Abstract Renal fibrosis is a manifestation of the progression of chronic kidney disease (CKD) and chronic inflammation is a main driver in the development of renal fibrosis. Yes-associated protein (YAP), acting as a transcriptional co-activator within the Hippo signaling pathway, has been implicated in renal fibrosis. Enhancer of zeste homolog 2 (EZH2) exhibits high expression level in renal fibrosis induced by unilateral ureteral obstruction (UUO), yet the interplay between YAP and EZH2 in renal fibrosis remains to be elucidated. ZLD1039, a selective inhibitor of EZH2, has demonstrated protective effects against cancer and acute kidney injury (AKI). In this study, we conducted a systemic pharmacological investigation to determine if ZLD1039 treatment mitigates UUO-induced renal inflammation and fibrosis through modulation of the Hippo-YAP pathway. Our results revealed that UUO triggered renal inflammation and collagen deposition, with significant activation of YAP. Notably, ZLD1039 treatment effectively alleviated renal inflammation and fibrosis, while inhibiting the expression and nuclear translocation of YAP. Mechanically, we observed a notable down-regulation of large tumor suppressor homolog 1 (LATS1) in parallel with the up-regulation of EZH2. Furthermore, inhibition of EZH2 by ZLD1039 was linked to the up-regulation of LATS1 expression and YAP inactivation. Similarly, in vitro pharmacological inhibition of EZH2 by ZLD1039 resulted in elevated LATS1 expression and diminished YAP activation. Collectively, our findings suggest that ZLD1039, a selective inhibitor of EZH2, likely attenuates renal inflammation and fibrosis probably by up-regulating LATS1 and inhibiting YAP activation. This mechanistic link between EZH2 and YAP provides a fresh perspective on treating renal fibrosis. |
| format | Article |
| id | doaj-art-2c8b8b245cab4684aaf782813afc9598 |
| institution | OA Journals |
| issn | 2662-8651 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Springer |
| record_format | Article |
| series | Molecular Biomedicine |
| spelling | doaj-art-2c8b8b245cab4684aaf782813afc95982025-08-20T02:30:49ZengSpringerMolecular Biomedicine2662-86512025-06-016111410.1186/s43556-025-00276-5The EZH2 selective inhibitor ZLD1039 attenuates UUO-induced renal fibrosis by suppressing YAP activationQingling Xia0Fujiang Xu1Lidan Zhang2Wenfei Ding3Jiang Liu4Jing Liu5Minhao Chen6Santao Ou7Yong Xu8Li Wen9Department of Nephrology, Sichuan Clinical Research Center for Nephropathy and Metabolic Vascular Diseases Key Laboratory of Sichuan Province, The Affiliated Hospital of Southwest Medical UniversityDepartment of Oncology, The Affiliated Hospital of Southwest Medical UniversityLaboratory of Anesthesia & Critical Care Medicine, Translational Neuroscience Center, West China Hospital of Sichuan UniversityDepartment of Nephrology, Sichuan Clinical Research Center for Nephropathy and Metabolic Vascular Diseases Key Laboratory of Sichuan Province, The Affiliated Hospital of Southwest Medical UniversityDepartment of Nephrology, Sichuan Clinical Research Center for Nephropathy and Metabolic Vascular Diseases Key Laboratory of Sichuan Province, The Affiliated Hospital of Southwest Medical UniversityDepartment of Urology, The Affiliated Hospital of Southwest Medical UniversityClinical Medical College, Southwest Medical UniversityDepartment of Nephrology, Sichuan Clinical Research Center for Nephropathy and Metabolic Vascular Diseases Key Laboratory of Sichuan Province, The Affiliated Hospital of Southwest Medical UniversityDepartment of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical UniversityDepartment of Nephrology, Sichuan Clinical Research Center for Nephropathy and Metabolic Vascular Diseases Key Laboratory of Sichuan Province, The Affiliated Hospital of Southwest Medical UniversityAbstract Renal fibrosis is a manifestation of the progression of chronic kidney disease (CKD) and chronic inflammation is a main driver in the development of renal fibrosis. Yes-associated protein (YAP), acting as a transcriptional co-activator within the Hippo signaling pathway, has been implicated in renal fibrosis. Enhancer of zeste homolog 2 (EZH2) exhibits high expression level in renal fibrosis induced by unilateral ureteral obstruction (UUO), yet the interplay between YAP and EZH2 in renal fibrosis remains to be elucidated. ZLD1039, a selective inhibitor of EZH2, has demonstrated protective effects against cancer and acute kidney injury (AKI). In this study, we conducted a systemic pharmacological investigation to determine if ZLD1039 treatment mitigates UUO-induced renal inflammation and fibrosis through modulation of the Hippo-YAP pathway. Our results revealed that UUO triggered renal inflammation and collagen deposition, with significant activation of YAP. Notably, ZLD1039 treatment effectively alleviated renal inflammation and fibrosis, while inhibiting the expression and nuclear translocation of YAP. Mechanically, we observed a notable down-regulation of large tumor suppressor homolog 1 (LATS1) in parallel with the up-regulation of EZH2. Furthermore, inhibition of EZH2 by ZLD1039 was linked to the up-regulation of LATS1 expression and YAP inactivation. Similarly, in vitro pharmacological inhibition of EZH2 by ZLD1039 resulted in elevated LATS1 expression and diminished YAP activation. Collectively, our findings suggest that ZLD1039, a selective inhibitor of EZH2, likely attenuates renal inflammation and fibrosis probably by up-regulating LATS1 and inhibiting YAP activation. This mechanistic link between EZH2 and YAP provides a fresh perspective on treating renal fibrosis.https://doi.org/10.1186/s43556-025-00276-5Enhancer of zeste homolog 2Large tumor suppressor 1Yes-associated protein 1InflammationRenal fibrosis |
| spellingShingle | Qingling Xia Fujiang Xu Lidan Zhang Wenfei Ding Jiang Liu Jing Liu Minhao Chen Santao Ou Yong Xu Li Wen The EZH2 selective inhibitor ZLD1039 attenuates UUO-induced renal fibrosis by suppressing YAP activation Molecular Biomedicine Enhancer of zeste homolog 2 Large tumor suppressor 1 Yes-associated protein 1 Inflammation Renal fibrosis |
| title | The EZH2 selective inhibitor ZLD1039 attenuates UUO-induced renal fibrosis by suppressing YAP activation |
| title_full | The EZH2 selective inhibitor ZLD1039 attenuates UUO-induced renal fibrosis by suppressing YAP activation |
| title_fullStr | The EZH2 selective inhibitor ZLD1039 attenuates UUO-induced renal fibrosis by suppressing YAP activation |
| title_full_unstemmed | The EZH2 selective inhibitor ZLD1039 attenuates UUO-induced renal fibrosis by suppressing YAP activation |
| title_short | The EZH2 selective inhibitor ZLD1039 attenuates UUO-induced renal fibrosis by suppressing YAP activation |
| title_sort | ezh2 selective inhibitor zld1039 attenuates uuo induced renal fibrosis by suppressing yap activation |
| topic | Enhancer of zeste homolog 2 Large tumor suppressor 1 Yes-associated protein 1 Inflammation Renal fibrosis |
| url | https://doi.org/10.1186/s43556-025-00276-5 |
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