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Inhibition of Setd7 protects against cardiomyocyte hypertrophy via inhibiting lipid oxidation

Acta Pharmacologica Sinica (2025)Cite this article

Abstract

Myocardial hypertrophy is one of the most prominent features of heart failure. SET domain-containing protein 7 (Setd7), a catalytic enzyme responsible for histone H3K4 methylation, has been implicated in various cardiac diseases. In this study we investigated whether Setd7 contributed to the development of cardiac hypertrophy. Male mice were subjected to a hypobaric hypoxic environment for 8 weeks; neonatal rat cardiomyocytes (NRCMs) exposed to hypoxia for 6 h. We showed that hypoxic stimulation significantly upregulated the expression levels of Setd7 along with the expression of hypertrophic markers ANP and BNP in NRCMs. By conducting loss- and gain-of-function assays, we demonstrated that Setd7 modulated the hypertrophic and inflammatory markers in hypoxic cardiomyocytes. We further revealed that Setd7-mediated activation of E2F1 (E2 promoter binding factor 1) triggered the expression of E3 ubiquitin protein ligases WWP2, which catalyzed the ubiquitination and degradation of glutathione peroxidase 4 (GPx4), a critical lipid peroxide-reducing enzyme. This degradation drove extensive lipid peroxidation, thereby exacerbating pathological cardiac hypertrophy. Notably, GPx4 inhibition by ras-selective lethal small molecule 3 (RSL3) abolished the antihypertrophic effects of Setd7 knockdown in cardiomyocytes, underscoring the pivotal role of lipid peroxidation in Setd7-mediated hypertrophic responses. In summary, Setd7 promotes hypoxia-induced cardiac hypertrophy through the Setd7-E2F1-WWP2-GPx4 signaling pathway, suggesting that targeting Setd7 is a promising therapeutic strategy to alleviate hypoxia-induced myocardial hypertrophy.

Graphical Abstract

Setd7 increases the enrichment of H3K4me2/3 on the E2F1 promoter region, mediating the transcriptional activation of E2F1. E2F1 further promotes WWP2 expression to trigger ubiquitination and degradation of GPx4 protein, ultimately causing widespread lipid peroxidation and boosting pathological cardiac hypertrophy.

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Fig. 1: Hypertrophic stimulation upregulates Setd7 expression.
Fig. 2: Setd7 promotes the pathological process of cardiomyocyte hypertrophy induced by hypoxia.
Fig. 3: Lipid peroxidation participates in Setd7-mediated cardiomyocyte hypertrophy.
Fig. 4: Setd7 deficiency alleviates hypoxia-induced cardiomyocyte hypertrophy through GPX4-mediated lipid peroxidation.
Fig. 5: WWP2 is involved in Setd7-mediated GPx4 degradation in hypoxic NRCMs.
Fig. 6: Setd7 modulates WWP2 expression by transcription factor E2F1.
Fig. 7: E2F1 modulates the progression of Setd7-mediated cardiac hypertrophy.

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References

  1. Nakamura M, Sadoshima J. Mechanisms of physiological and pathological cardiac hypertrophy. Nat Rev Cardiol. 2018;15:387–407.

    Article  CAS  PubMed  Google Scholar 

  2. Groenewegen A, Rutten FH, Mosterd A, Hoes AW. Epidemiology of heart failure. Eur J Heart Fail. 2020;22:1342–56.

    Article  PubMed  Google Scholar 

  3. Adamo L, Rocha-Resende C, Prabhu SD, Mann DL. Reappraising the role of inflammation in heart failure. Nat Rev Cardiol. 2020;17:269–85.

    Article  PubMed  Google Scholar 

  4. Jiang F, Yin K, Wu K, Zhang M, Wang S, Cheng H, et al. The mechanosensitive Piezo1 channel mediates heart mechano-chemo transduction. Nat Commun. 2021;12:869.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Savarese G, Becher PM, Lund LH, Seferovic P, Rosano GMC, Coats AJS. Global burden of heart failure: a comprehensive and updated review of epidemiology. Cardiovasc Res. 2023;118:3272–87.

    Article  PubMed  Google Scholar 

  6. Yin H, Xu L, Porter NA. Free radical lipid peroxidation: mechanisms and analysis. Chem Rev. 2011;111:5944–72.

    Article  CAS  PubMed  Google Scholar 

  7. Gaschler MM, Stockwell BR. Lipid peroxidation in cell death. Biochem Biophys Res Commun. 2017;482:419–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Chen F, Kang R, Tang D, Liu J. Ferroptosis: principles and significance in health and disease. J Hematol Oncol. 2024;17:41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149:1060–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, et al. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell. 2017;171:273–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zhang Q, Luo Y, Peng L, Rong X, Liu Y, Li J, et al. Ferroptosis in cardiovascular diseases: role and mechanism. Cell Biosci. 2023;13:226.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Liu X, Chen Z, Xu C, Leng X, Cao H, Ouyang G, et al. Repression of hypoxia-inducible factor α signaling by Set7-mediated methylation. Nucleic Acids Res. 2015;43:5081–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lv J, Wu Q, Li K, Bai K, Yu H, Zhuang J, et al. Lysine N-methyltransferase SETD7 promotes bladder cancer progression and immune escape via STAT3/PD-L1 cascade. Int J Biol Sci. 2023;19:3744–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Oudhoff MJ, Braam MJS, Freeman SA, Wong D, Rattray DG, Wang J, et al. SETD7 controls intestinal regeneration and tumorigenesis by regulating Wnt/β-Catenin and Hippo/YAP Signaling. Dev Cell. 2016;37:47–57.

    Article  CAS  PubMed  Google Scholar 

  15. Ambrosini S, Montecucco F, Kolijn D, Pedicino D, Akhmedov A, Mohammed SA, et al. Methylation of the Hippo effector YAP by the methyltransferase SETD7 drives myocardial ischaemic injury: a translational study. Cardiovasc Res. 2023;118:3374–85.

    Article  PubMed  Google Scholar 

  16. Wang J, Deng B, Liu Q, Huang Y, Chen W, Li J, et al. Pyroptosis and ferroptosis induced by mixed lineage kinase 3 (MLK3) signaling in cardiomyocytes are essential for myocardial fibrosis in response to pressure overload. Cell Death Dis. 2020;11:574.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Yin Z, Ding G, Chen X, Qin X, Xu H, Zeng B, et al. Beclin1 haploinsufficiency rescues low ambient temperature-induced cardiac remodeling and contractile dysfunction through inhibition of ferroptosis and mitochondrial injury. Metabolism. 2020;113:154397.

    Article  CAS  PubMed  Google Scholar 

  18. Park TJ, Park JH, Lee GS, Lee JY, Shin JH, Kim MW, et al. Quantitative proteomic analyses reveal that GPX4 downregulation during myocardial infarction contributes to ferroptosis in cardiomyocytes. Cell Death Dis. 2019;10:835.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Wang Y, Yan S, Liu X, Deng F, Wang P, Yang L, et al. PRMT4 promotes ferroptosis to aggravate doxorubicin-induced cardiomyopathy via inhibition of the Nrf2/GPX4 pathway. Cell Death Differ. 2022;29:1982–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, et al. Regulation of ferroptotic cancer cell death by GPX4. Cell. 2014;156:317–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Liu Q, Song T, Chen B, Zhang J, Li W. Ferroptosis of brain microvascular endothelial cells contributes to hypoxia-induced blood-brain barrier injury. FASEB J. 2023;37:e22874.

    Article  CAS  PubMed  Google Scholar 

  22. Cheng K, Yang G, Huang M, Huang Y, Wang C. Exogenous 1,25(OH)(2)D(3)/VD(3) counteracts RSL3-Induced ferroptosis by enhancing antioxidant capacity and regulating iron ion transport: Using zebrafish as a model. Chem Biol Interact. 2024;387:110828.

    Article  CAS  PubMed  Google Scholar 

  23. Chou PC, Liu CM, Weng CH, Yang KC, Cheng ML, Lin YC, et al. Fibroblasts drive metabolic reprogramming in pacemaker cardiomyocytes. Circ Res. 2022;131:6–20.

    Article  CAS  PubMed  Google Scholar 

  24. Dassanayaka S, Brittian KR, Jurkovic A, Higgins LA, Audam TN, Long BW, et al. E2f1 deletion attenuates infarct-induced ventricular remodeling without affecting O-GlcNAcylation. Basic Res Cardiol. 2019;114:28.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Ea CK, Baltimore D. Regulation of NF-kappaB activity through lysine monomethylation of p65. Proc Natl Acad Sci USA. 2009;106:18972–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kontaki H, Talianidis I. Lysine methylation regulates E2F1-induced cell death. Mol Cell. 2010;39:152–60.

    Article  CAS  PubMed  Google Scholar 

  27. Kouskouti A, Scheer E, Staub A, Tora L, Talianidis I. Gene-specific modulation of TAF10 function by SET9-mediated methylation. Mol Cell. 2004;14:175–82.

    Article  CAS  PubMed  Google Scholar 

  28. Wang H, Cao R, Xia L, Erdjument-Bromage H, Borchers C, Tempst P, et al. Purification and functional characterization of a histone H3-lysine 4-specific methyltransferase. Mol Cell. 2001;8:1207–17.

    Article  CAS  PubMed  Google Scholar 

  29. Chuikov S, Kurash JK, Wilson JR, Xiao B, Justin N, Ivanov GS, et al. Regulation of p53 activity through lysine methylation. Nature. 2004;432:353–60.

    Article  CAS  PubMed  Google Scholar 

  30. Torella D, Salerno N, Cianflone E. SETD7 methyltransferase is a key druggable target for effective cardioprotection from myocardial ischaemic injury. Cardiovasc Res. 2023;118:3269–71.

    Article  PubMed  Google Scholar 

  31. Mohammed SA, Gorica E, Albiero M, Karsai G, Mengozzi A, Caravaggi CM, et al. Targeting SETD7 rescues diabetes-induced impairment of angiogenic response by transcriptional repression of semaphorin-3G. Diabetes. 2025;74:969–82.

    Article  PubMed  Google Scholar 

  32. Wang J, Tan S, Zhang Y, Xu J, Li Y, Cheng Q, et al. Set7/9 aggravates ischemic brain injury via enhancing glutamine metabolism in a blocking Sirt5 manner. Cell Death Differ. 2024;31:511–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Bichmann M, Prat Oriol N, Ercan-Herbst E, Schöndorf DC, Gomez Ramos B, Schwärzler V, et al. SETD7-mediated monomethylation is enriched on soluble Tau in Alzheimer’s disease. Mol Neurodegener. 2021;16:46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Peng L, Song Z, Zhao C, Abuduwufuer K, Wang Y, Wen Z, et al. Increased soluble epoxide hydrolase activity positively correlates with mortality in heart failure patients with preserved ejection fraction: evidence from metabolomics. Phenomics. 2023;3:34–49.

    Article  CAS  PubMed  Google Scholar 

  35. Alzahrani AM, Rajendran P, Veeraraghavan VP, Hanieh H. Cardiac protective effect of kirenol against doxorubicin-induced cardiac hypertrophy in H9c2 cells through Nrf2 signaling via PI3K/AKT pathways. Int J Mol Sci. 2021;22:3269.

  36. Baba SP, Zhang D, Singh M, Dassanayaka S, Xie Z, Jagatheesan G, et al. Deficiency of aldose reductase exacerbates early pressure overload-induced cardiac dysfunction and autophagy in mice. J Mol Cell Cardiol. 2018;118:183–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Seiler A, Schneider M, Förster H, Roth S, Wirth EK, Culmsee C, et al. Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent- and AIF-mediated cell death. Cell Metab. 2008;8:237–48.

    Article  CAS  PubMed  Google Scholar 

  38. Sun X, Zhang Q, Lin X, Shu P, Gao X, Shen K. Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination. Cell Death Dis. 2023;14:839.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Orian L, Mauri P, Roveri A, Toppo S, Benazzi L, Bosello-Travain V, et al. Selenocysteine oxidation in glutathione peroxidase catalysis: an MS-supported quantum mechanics study. Free Radic Biol Med. 2015;87:1–14.

    Article  CAS  PubMed  Google Scholar 

  40. Wang Z, Xia Y, Wang Y, Zhu R, Li H, Liu Y, et al. The E3 ligase TRIM26 suppresses ferroptosis through catalyzing K63-linked ubiquitination of GPX4 in glioma. Cell Death Dis. 2023;14:695.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Sun X, Huang N, Li P, Dong X, Yang J, Zhang X, et al. TRIM21 ubiquitylates GPX4 and promotes ferroptosis to aggravate ischemia/reperfusion-induced acute kidney injury. Life Sci. 2023;321:121608.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Chen X, Ma J, Wang ZW, Wang Z. The E3 ubiquitin ligases regulate inflammation in cardiovascular diseases. Semin Cell Dev Biol. 2024;154:167–74.

    Article  CAS  PubMed  Google Scholar 

  43. Zhang N, Zhang Y, Qian H, Wu S, Cao L, Sun Y. Selective targeting of ubiquitination and degradation of PARP1 by E3 ubiquitin ligase WWP2 regulates isoproterenol-induced cardiac remodeling. Cell Death Differ. 2020;27:2605–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Song Y, Ren X, Gao F, Li F, Zhou J, Chen J, et al. LINC01588 regulates WWP2-mediated cardiomyocyte injury by interacting with HNRNPL. Environ Toxicol. 2022;37:1629–41.

    Article  CAS  PubMed  Google Scholar 

  45. Ertosun MG, Hapil FZ, Osman Nidai O. E2F1 transcription factor and its impact on growth factor and cytokine signaling. Cytokine Growth Factor Rev. 2016;31:17–25.

    Article  PubMed  Google Scholar 

  46. Wu M, Zhou J, Cheng M, Boriboun C, Biyashev D, Wang H, et al. E2F1 suppresses cardiac neovascularization by down-regulating VEGF and PlGF expression. Cardiovasc Res. 2014;104:412–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Liao R, Xie B, Cui J, Qi Z, Xue S, Wang Y. E2F transcription factor 1 (E2F1) promotes the transforming growth factor TGF-β1 induced human cardiac fibroblasts differentiation through promoting the transcription of CCNE2 gene. Bioengineered. 2021;12:6869–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

The working model of this study was drawn using Biorender (www.biorender.com). This work was supported by National Key R&D Program of China (2023YFA1801200) and Science and Technology Commission of Shanghai Municipality (22S11902700).

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  1. These authors contributed equally: Hai-bi Su, Jing-huan Wang, Yu-yu Zhang

Authors and Affiliations

  1. Phenome Research Center of TCM, Department of Traditional Chinese Medicine, Shanghai Pudong Hospital, Pharmacophenomics Laboratory, Human Phenome Institute, Fudan University, Shanghai, 200120, China

    Hai-bi Su, Jing-huan Wang, Yu-yu Zhang, Jie Xu, Jia-yao Liu, Yu-hui Li, Chen-xi Xiao, Cai-yun Wang, Jun Chang & Xin-hua Liu

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HBS, JHW and YYZ performed experiments, analyzed the data and wrote the manuscript. JX contributed to in vitro experiments. JYL, YHL, CXX and CYW contributed to the animal experiments. XHL and JC designed the experiments and supervised the project. All authors read and approved the final manuscript.

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Correspondence to Jun Chang or Xin-hua Liu.

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Su, Hb., Wang, Jh., Zhang, Yy. et al. Inhibition of Setd7 protects against cardiomyocyte hypertrophy via inhibiting lipid oxidation. Acta Pharmacol Sin (2025). https://doi.org/10.1038/s41401-025-01626-3

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