HMC ameliorates myocardial ischaemia-reperfusion injury through suppressing cuproptosis via the de-ubiquitination and stabilization of ATP7A

doi:10.1111/bph.70171

. 2025 Aug 14.

doi: 10.1111/bph.70171. Online ahead of print.

HMC ameliorates myocardial ischaemia-reperfusion injury through suppressing cuproptosis via the de-ubiquitination and stabilization of ATP7A

Jia-Bao Su¹, You-Yi Zhuang², Ming-Heng Liu¹, Guo Chen², Min Wei², Bing-Xin Chen¹, Le Yang², Yun-Feng Ji², Chuan Zhu², Xue-Xue Zhu², Ji-Ru Zhang¹, Hai-Jian Sun^{1

2

3}

Affiliations

¹ Department of Anesthesiology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, China.
² Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, Medical Center, Jiangnan University, Wuxi, China.
³ State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.

PMID: 40813128
DOI: 10.1111/bph.70171

HMC ameliorates myocardial ischaemia-reperfusion injury through suppressing cuproptosis via the de-ubiquitination and stabilization of ATP7A

Jia-Bao Su et al. Br J Pharmacol. 2025.

. 2025 Aug 14.

doi: 10.1111/bph.70171. Online ahead of print.

Authors

Jia-Bao Su¹, You-Yi Zhuang², Ming-Heng Liu¹, Guo Chen², Min Wei², Bing-Xin Chen¹, Le Yang², Yun-Feng Ji², Chuan Zhu², Xue-Xue Zhu², Ji-Ru Zhang¹, Hai-Jian Sun^{1

2

3}

Affiliations

¹ Department of Anesthesiology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, China.
² Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, Medical Center, Jiangnan University, Wuxi, China.
³ State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.

PMID: 40813128
DOI: 10.1111/bph.70171

Abstract

Background and purpose: Myocardial ischaemia-reperfusion injury (MI/RI) is a major contributor to poor prognosis following revascularization in myocardial infarction patients, yet targeted therapies remain elusive. While hesperidin methyl chalcone (HMC) demonstrates antioxidant and vasoprotective properties, its role in modulating regulated cell death pathways during MI/RI is undefined. This study investigates the cardioprotective effects of HMC against MI/RI and its underlying mechanisms.

Experimental approach: Hypoxia/reoxygenation (H/R) models in H9c2 cardiomyocytes and a model of MI/RI in mice were employed. The effects of HMC on cardiac performance, copper flux analysis, ubiquitination assays and molecular docking, mitochondrial integrity and cell death modalities in response to MI/RI were examined.

Key results: HMC pretreatment exhibited significant cardioprotection, reducing infarct size and improving cardiac function in MI/RI mice. Mechanistically, HMC specifically attenuated cuproptosis, as evidenced by decreased copper overload and downregulation of cuproptosis effectors, mimicking the action of the copper chelator ammonium tetrathiomolybdate (ATTM). Crucially, the cuproptosis inducer elesclomol-Cu (Es-Cu) abolished the cardioprotective effects of HMC. Furthermore, HMC interacted with the E3 ubiquitin ligase MARCHF7, and disrupted the complex of MARCHF7/ATP7A, thereby reducing ubiquitination and proteasomal degradation of the copper exporter ATP7A. The stabilization of ATP7A enhanced copper efflux, alleviating cuproptosis, oxidative stress, inflammation and mitochondrial damage induced by MI/RI.

Conclusions and implications: Our work unveils a ubiquitin-regulated copper homeostasis axis in MI/RI. By targeting MARCHF7-ATP7A interaction, HMC sustains copper export machinery to combat cuproptosis-driven injury. These findings position HMC as a novel therapeutic candidate for MI/RI through regulating ubiquitination-dependent regulation of copper homeostasis.

Keywords: cuproptosis; mitochondrial function; myocardial ischaemia–reperfusion injury; oxidative stress; ubiquitination.

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References

REFERENCES

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1. Alexander, S. P. H., Fabbro, D., Kelly, E., Mathie, A. A., Peters, J. A., Veale, E. L., Armstrong, J. F., Faccenda, E., Harding, S. D., Davies, J. A., Amarosi, L., Anderson, C. M. H., Beart, P. M., Broer, S., Dawson, P. A., Gyimesi, G., Hagenbuch, B., Hammond, J. R., Hancox, J. C., … Verri, T. (2023). The Concise Guide to PHARMACOLOGY 2023/24: Transporters. British Journal of Pharmacolog, 180, S374–S469. https://doi.org/10.1111/bph.16182
1. Alexander, S. P. H., Kelly, E., Mathie, A. A., Peters, J. A., Veale, E. L., Armstrong, J. F., Buneman, O. P., Faccenda, E., Harding, S. D., Spedding, M., Cidlowski, J. A., Fabbro, D., Davenport, A. P., Striessnig, J., Davies, J. A., Ahlers‐Dannen, K. E., Alqinyah, M., Arumugam, T. V., Bodle, C., … Zolghadri, Y. (2023). The Concise Guide to PHARMACOLOGY 2023/24: Introduction and Other Protein Targets. British Journal of Pharmacology, 180, S1–S22. https://doi.org/10.1111/bph.16176
1. Alexander, S. P. H., Roberts, R. E., Broughton, B. R. S., Sobey, C. G., George, C. H., Stanford, S. C., Cirino, G., Docherty, J. R., Giembycz, M. A., Hoyer, D., Insel, P. A., Izzo, A. A., Ji, Y., MacEwan, D. J., Mangum, J., Wonnacott, S., & Ahluwalia, A. (2018). Goals and practicalities of immunoblotting and immunohistochemistry: A guide for submission to the British Journal of Pharmacology. British Journal of Pharmacology, 175(3), 407–411. https://doi.org/10.1111/bph.14112

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[1] Alexander, S. P. H., Fabbro, D., Kelly, E., Mathie, A. A., Peters, J. A., Veale, E. L., Armstrong, J. F., Faccenda, E., Harding, S. D., Davies, J. A., Beuve, A., Brouckaert, P., Bryant, C., Burnett, J. C., Farndale, R. W., Friebe, A., Garthwaite, J., Hobbs, A. J., Jarvis, G. E., … Waldman, S. A. (2023). The Concise Guide to PHARMACOLOGY 2023/24: Catalytic receptors. British Journal of Pharmacology, 180, S241–S288. https://doi.org/10.1111/bph.16180

[2] Alexander, S. P. H., Fabbro, D., Kelly, E., Mathie, A. A., Peters, J. A., Veale, E. L., Armstrong, J. F., Faccenda, E., Harding, S. D., Davies, J. A., Beuve, A., Brouckaert, P., Bryant, C., Burnett, J. C., Farndale, R. W., Friebe, A., Garthwaite, J., Hobbs, A. J., Jarvis, G. E., … Waldman, S. A. (2023). The Concise Guide to PHARMACOLOGY 2023/24: Catalytic receptors. British Journal of Pharmacology, 180, S241–S288. https://doi.org/10.1111/bph.16180

[3] Alexander, S. P. H., Fabbro, D., Kelly, E., Mathie, A. A., Peters, J. A., Veale, E. L., Armstrong, J. F., Faccenda, E., Harding, S. D., Davies, J. A., Annett, S., Boison, D., Burns, K. E., Dessauer, C., Gertsch, J., Helsby, N. A., Izzo, A. A., Ostrom, R., Papapetropoulos, A., … Wong, S. S. (2023). The concise guide to PHARMACOLOGY 2023/24: Enzymes. British Journal of Pharmacology, 180, S289–S373. https://doi.org/10.1111/bph.16181

[4] Alexander, S. P. H., Fabbro, D., Kelly, E., Mathie, A. A., Peters, J. A., Veale, E. L., Armstrong, J. F., Faccenda, E., Harding, S. D., Davies, J. A., Annett, S., Boison, D., Burns, K. E., Dessauer, C., Gertsch, J., Helsby, N. A., Izzo, A. A., Ostrom, R., Papapetropoulos, A., … Wong, S. S. (2023). The concise guide to PHARMACOLOGY 2023/24: Enzymes. British Journal of Pharmacology, 180, S289–S373. https://doi.org/10.1111/bph.16181

[5] Alexander, S. P. H., Fabbro, D., Kelly, E., Mathie, A. A., Peters, J. A., Veale, E. L., Armstrong, J. F., Faccenda, E., Harding, S. D., Davies, J. A., Amarosi, L., Anderson, C. M. H., Beart, P. M., Broer, S., Dawson, P. A., Gyimesi, G., Hagenbuch, B., Hammond, J. R., Hancox, J. C., … Verri, T. (2023). The Concise Guide to PHARMACOLOGY 2023/24: Transporters. British Journal of Pharmacolog, 180, S374–S469. https://doi.org/10.1111/bph.16182

[6] Alexander, S. P. H., Fabbro, D., Kelly, E., Mathie, A. A., Peters, J. A., Veale, E. L., Armstrong, J. F., Faccenda, E., Harding, S. D., Davies, J. A., Amarosi, L., Anderson, C. M. H., Beart, P. M., Broer, S., Dawson, P. A., Gyimesi, G., Hagenbuch, B., Hammond, J. R., Hancox, J. C., … Verri, T. (2023). The Concise Guide to PHARMACOLOGY 2023/24: Transporters. British Journal of Pharmacolog, 180, S374–S469. https://doi.org/10.1111/bph.16182

[7] Alexander, S. P. H., Kelly, E., Mathie, A. A., Peters, J. A., Veale, E. L., Armstrong, J. F., Buneman, O. P., Faccenda, E., Harding, S. D., Spedding, M., Cidlowski, J. A., Fabbro, D., Davenport, A. P., Striessnig, J., Davies, J. A., Ahlers‐Dannen, K. E., Alqinyah, M., Arumugam, T. V., Bodle, C., … Zolghadri, Y. (2023). The Concise Guide to PHARMACOLOGY 2023/24: Introduction and Other Protein Targets. British Journal of Pharmacology, 180, S1–S22. https://doi.org/10.1111/bph.16176

[8] Alexander, S. P. H., Kelly, E., Mathie, A. A., Peters, J. A., Veale, E. L., Armstrong, J. F., Buneman, O. P., Faccenda, E., Harding, S. D., Spedding, M., Cidlowski, J. A., Fabbro, D., Davenport, A. P., Striessnig, J., Davies, J. A., Ahlers‐Dannen, K. E., Alqinyah, M., Arumugam, T. V., Bodle, C., … Zolghadri, Y. (2023). The Concise Guide to PHARMACOLOGY 2023/24: Introduction and Other Protein Targets. British Journal of Pharmacology, 180, S1–S22. https://doi.org/10.1111/bph.16176

[9] Alexander, S. P. H., Roberts, R. E., Broughton, B. R. S., Sobey, C. G., George, C. H., Stanford, S. C., Cirino, G., Docherty, J. R., Giembycz, M. A., Hoyer, D., Insel, P. A., Izzo, A. A., Ji, Y., MacEwan, D. J., Mangum, J., Wonnacott, S., & Ahluwalia, A. (2018). Goals and practicalities of immunoblotting and immunohistochemistry: A guide for submission to the British Journal of Pharmacology. British Journal of Pharmacology, 175(3), 407–411. https://doi.org/10.1111/bph.14112

[10] Alexander, S. P. H., Roberts, R. E., Broughton, B. R. S., Sobey, C. G., George, C. H., Stanford, S. C., Cirino, G., Docherty, J. R., Giembycz, M. A., Hoyer, D., Insel, P. A., Izzo, A. A., Ji, Y., MacEwan, D. J., Mangum, J., Wonnacott, S., & Ahluwalia, A. (2018). Goals and practicalities of immunoblotting and immunohistochemistry: A guide for submission to the British Journal of Pharmacology. British Journal of Pharmacology, 175(3), 407–411. https://doi.org/10.1111/bph.14112

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HMC ameliorates myocardial ischaemia-reperfusion injury through suppressing cuproptosis via the de-ubiquitination and stabilization of ATP7A

Affiliations

HMC ameliorates myocardial ischaemia-reperfusion injury through suppressing cuproptosis via the de-ubiquitination and stabilization of ATP7A

Authors

Affiliations

Abstract

References

REFERENCES

Grants and funding

LinkOut - more resources

Full Text Sources