2. Academic Validation
  3. Cardiomyocyte Cyclin-dependent kinase 9 directly binds to and phosphorylates NF-κB p65 subunit to drive cardiac inflammation and remodeling

Cardiomyocyte Cyclin-dependent kinase 9 directly binds to and phosphorylates NF-κB p65 subunit to drive cardiac inflammation and remodeling

  • Nat Commun. 2026 Mar 24;17(1):5036. doi: 10.1038/s41467-026-70410-6.
Shiju Ye # 1 2 3 4,  Yanbo Zhao # 2 3,  Hanxiao Tu # 5,  Xue Han 1,  Tong Liu 6,  Yingchao Gong 2 3,  Jiangting Lu 2 3,  Tingting Jin 2 3,  Wu Luo 1 4,  Xuefeng Qu 1,  Dongwu Lai 2 3,  Guosheng Fu 7 8 9,  Guang Liang 10 11
Affiliations

Affiliations

  • 1 International Laboratory of Cardiovascular Diseases, School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, China.
  • 2 Department of Cardiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
  • 3 Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Hangzhou, Zhejiang, China.
  • 4 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 5 Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
  • 6 School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, Hangzhou, Zhejiang, China.
  • 7 Department of Cardiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. [email protected].
  • 8 Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Hangzhou, Zhejiang, China. [email protected].
  • 9 School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, Hangzhou, Zhejiang, China. [email protected].
  • 10 International Laboratory of Cardiovascular Diseases, School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, China. [email protected].
  • 11 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China. [email protected].
  • # Contributed equally.
PMID: 41876530 DOI: 10.1038/s41467-026-70410-6
Abstract

Hypertensive heart failure highlights an urgent need for effective therapeutic strategies. Protein kinases regulate multiple pathways in cardiac pathophysiology and may provide promising therapeutic targets. Here, we identified a Cyclin-dependent kinase, CDK9, promoting inflammation and cardiac remodeling in terminally differentiated cardiomyocytes. Firstly, kinase enrichment analysis and experimental evidence revealed CDK9 phosphorylation at Thr-186 in both human and mouse hypertrophic heart tissues. CDK9 loss of function via T186A mutation in cardiomyocytes attenuated Ang II-induced heart remodeling and NF-κB-mediated inflammation, whereas CDK9 overactivation by T186E mutation induces. This regulatory function of CDK9 in cardiac remodeling is cell cycle-independent. Further studies demonstrate that the kinase domain of CDK9 directly binds to NF-κB P65 protein, which leads to the CDK9/P65 complex nuclear translocation, P65 phosphorylation, and transcription of inflammatory and hypertrophic genes in cardiomyocytes. This process requires CDK9 Thr-186 phosphorylation and Cyclin T1 presence, but is independent on IKKβ and CDK9-RNAPII pathways. Pharmacological inhibition of CDK9 phosphorylation significantly attenuated Ang II-induced cardiac inflammation, remodeling, and dysfunction in mice. Collectively, Ang II-activated CDK9 directly binds to and phosphorylates P65 to drive cardiac inflammation and remodeling. This study identifies CDK9 as a potential target in heart failure therapeutics.

Figures
Products