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RNF220 mediates K63-linked polyubiquitination of STAT3 and aggravates pathological cardiac hypertrophy

Cell Death & Differentiation (2025)Cite this article

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Abstract

Pathological cardiac hypertrophy serves as an independent risk factor for heart failure, which is the final stage of numerous cardiovascular diseases. However, the molecular regulatory mechanisms underlying this pathological process are still poorly characterized. The ubiquitin-proteasome system (UPS) is known to influence the development of pathological cardiac hypertrophy by precisely controlling protein function, localization, and proteostasis. The E3 ubiquitin ligase ring finger protein 220 (RNF220), a component of the UPS, was chosen as the research subject to investigate its role in pathological cardiac hypertrophy. Using Ang II-induced cardiac hypertrophy models combined with RNF220 knockout mice, RNF220 overexpression mice, and primary cardiomyocytes to examine the molecular mechanisms by which RNF220 governs pathological cardiac hypertrophy. We found that RNF220 deficiency promotes resistance to angiotensin II infusion by suppressing myocardial hypertrophy and fibrosis, whereas RNF220 overexpression aggravated cardiac dysfunction and hypertrophic responses. Moreover, using proteomic mass spectrometry and co-immunoprecipitation (Co-IP) experiments, we identified a functional interaction between RNF220 and STAT3. Mechanistically, RNF220 directly binds to the SH2 and TAD structural domains of STAT3 via its N-terminal domain, specifically facilitating K63-linked polyubiquitination at lysine residues 615, 626, 631, and 642 of STAT3, thereby stabilizing its protein to drive pro-hypertrophic responses. Critical rescue experiments demonstrated that STAT3 inhibitors or gene silencing effectively restored the ventricular hypertrophy phenotype caused by RNF220 overexpression. Collectively, these findings reveal a novel mechanism by which RNF220 drives pathological myocardial hypertrophy by regulating STAT3 ubiquitination, indicating a potential therapeutic target for heart failure intervention.

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Fig. 1: RNF220 is upregulated in pathological cardiac hypertrophy.
Fig. 2: RNF220 deficiency attenuates Ang II-induced cardiac hypertrophy.
Fig. 3: RNF220 regulates Ang II-induced cardiomyocyte hypertrophy in vitro.
Fig. 4: Interaction between RNF220 and STAT3.
Fig. 5: RNF220 regulates STAT3 protein stability via K63-linked ubiquitination.
Fig. 6: RNF220 regulates STAT3 phosphorylation, nuclear translocation, and transcriptional activity via ubiquitination.
Fig. 7: STAT3 inhibition and targeting its SH2 domain reverse RNF220 overexpression-induced cardiac hypertrophy and fibrosis.

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The data underlying this article will be shared on reasonable request to the corresponding author.

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Acknowledgements

We thank Mengmeng Zhao (Central Hospital Affiliated Shandong First Medical University, Jinan) for ubiquitin plasmids; Tianning Wang (Central Hospital Affiliated Shandong First Medical University, Jinan) for plasmid construction and technical support.

Funding

This work was supported by grants from the Natural Science Foundation of Shandong Province (No. ZR2024MH214) and Qingdao Outstanding Health Professional Development Fund.

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Author notes

  1. These authors contributed equally: Jun Guan, Hongyan Dai.

Authors and Affiliations

  1. Department of Cardiology, Qingdao University, Qingdao, 266071, China

    Yan Gao, Xuepin Chen, Jun Guan & Hongyan Dai

  2. Department of Cardiology, Qingdao Municipal Hospital, Qingdao, 266011, China

    Yan Gao, Xuepin Chen, Nuo Li, Jun Guan & Hongyan Dai

  3. Department of Cardiology, Central Hospital Affiliated Shandong First Medical University, Jinan, 250013, China

    Yan Gao & Zhuo Zhao

  4. School of Clinical Medicine, Shandong Second Medical University, Weifang, 261053, China

    Nuo Li

  5. Research Center of Translational Medicine, Central Hospital Affiliated Shandong First Medical University, Jinan, 250013, China

    Ying Li

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Contributions

YG designed the study, conducted the major experiments, and drafted the manuscript. ZZ performed the data analysis. XPC, NL and YL assisted with partial experiments. As the project leaders, JG and HYD co-supervised the research, contributed to manuscript writing, provided experimental guidance, and secured funding.

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Correspondence to Jun Guan or Hongyan Dai.

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Ethics

All animal experiments were approved by the Animal Welfare and Ethics Committee of Jinan Central Hospital (Approval Document No. JNCHIACUC2024-74, JNCHIACUC2024-75) and were conducted in strict accordance with institutional guidelines.

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Gao, Y., Zhao, Z., Chen, X. et al. RNF220 mediates K63-linked polyubiquitination of STAT3 and aggravates pathological cardiac hypertrophy. Cell Death Differ (2025). https://doi.org/10.1038/s41418-025-01614-4

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