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Cardiac fibroblast Foxm1 deficiency prevents pressure overload-induced cardiac remodeling via the Usp10/MKK6-p38γ MAPK axis

Cell Death & Differentiation (2025)Cite this article

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Abstract

Cardiac fibroblasts (CFs) activation plays a crucial role in cardiac remodeling. However, the molecular mechanisms underlying the fibroblast-to-myofibroblast transition remain largely unknown. Here we found elevated Foxm1 expression in human heart failure (HF) samples as well as in the mouse cardiac remodeling model. CFs were the primary cell type responsible for Foxm1 upregulation. Foxm1 genetic knockout in CFs or myofibroblasts significantly attenuated TAC-induced cardiac remodeling and HF. Conversely, conditional overexpression of Foxm1 in CFs resulted in more severe pathological cardiac remodeling and dysfunction by TAC. Combined RNA-sequencing and MS analysis revealed that Foxm1 promoted p38 mitogen-activated protein kinase (MAPK) signalling pathway. Mechanically, Foxm1 not only upregulates USP10 to reduce the ubiquitination and degradation of p38γ but also directly drives the expression of MKK6 to increase the phosphorylation levels of p38, thereby acting as a dual amplifier for p38 activation. Genetic knockout of p38γ ameliorated the exacerbated TAC-induced cardiac remodeling in mice with Foxm1 overexpression in CFs. Our findings suggest that targeting the Foxm1-USP10/MKK6-p38γ MAPK axis may represent a new potential therapeutic strategy against pathological cardiac remodeling and HF.

Foxm1 promotes the CFs activation during TAC-induced pathological cardiac remodeling through modulation of the USP10/MKK6-p38γ MAPK signalling pathway. Pro-fibrotic stimuli increase Foxm1 expression, which upregulates USP10 to reduce the ubiquitination and degradation of p38γ but also directly drives the expression of MKK6 to increase the phosphorylation levels of p38, thereby acting as a dual amplifier for p38 activation and promoting fibroblast-to-myofibroblast transition. Moreover, genetic knockout of p38γ mitigates exacerbated TAC-induced pathological cardiac remodeling in mice with Foxm1 overexpression in CFs.

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Fig. 1: Foxm1 expression is increased in cardiac remodeling.
Fig. 2: Foxm1 deficiency in CFs attenuates TAC-induced cardiac remodeling and dysfunction.
Fig. 3: Foxm1 overexpression in CFs exacerbates the progression of cardiac remodeling under pressure overload.
Fig. 4: Foxm1 deficiency in myofibroblasts attenuates TAC-induced cardiac remodeling and dysfunction.
Fig. 5: Foxm1 regulates Ang II-induced fibroblast-to-myofibroblast transition in vitro.
Fig. 6: Foxm1-promoted CFs differentiation requires p38-MAPK activation.
Fig. 7: Usp10 interacts with p38γ to promote its deubiquitination and expression.
Fig. 8: p38γ knockout in vivo rescues the effect of Foxm1 overexpression on TAC-induced cardiac remodeling and dysfunction.

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Data availability

The sequencing data and proteomics data have been deposited in the NCBI Gene Expression Omnibus (GEO) under accession number GSE248447 and ProteomeXchange under accession number PXD050300. Full-length, uncropped original Western blots have been uploaded. All other data presented in the paper are available from the corresponding author upon reasonable request.

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Acknowledgements

This work was supported by the China National Natural Science Foundation (grant number 82470271 to Shuai Song), Basic Science Center Project (grant number T2288101 to Junbo Ge), the National Natural Science Foundation (grant number 82130010 to Aijun Sun), the Shanghai Clinical Research Center for Interventional Medicine (grant number 19MC1910300 to Junbo Ge), the National Natural Science Foundation (grant number 82370261 to Hao Lu) and the National Natural Science Foundation (grant number 82470377 to Xiaochun Zhang). This work was supported by the Medical Science Data Center of Fudan University.

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  1. These authors contributed equally: Shuai Song, Xiaokai Zhang, Zihang Huang, Linqi Zeng.

Authors and Affiliations

  1. Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China

    Shuai Song, Xiaokai Zhang, Zihang Huang, Linqi Zeng, Fengze Cai, Tongyao Wang, Yining Song, Jiahao Guo, Mohan Li, Chenyan Liu, Xinyu Weng, Li Shen, Xiaochun Zhang, Hao Lu, Aijun Sun & Junbo Ge

  2. State Key Laboratory of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China

    Shuai Song, Xiaokai Zhang, Zihang Huang, Linqi Zeng, Fengze Cai, Tongyao Wang, Yining Song, Jiahao Guo, Mohan Li, Chenyan Liu, Xinyu Weng, Li Shen, Xiaochun Zhang, Hao Lu, Aijun Sun & Junbo Ge

  3. Key Laboratory of Viral Heart Diseases, National Health Commission, Shanghai, China

    Shuai Song, Xiaokai Zhang, Zihang Huang, Linqi Zeng, Fengze Cai, Tongyao Wang, Yining Song, Jiahao Guo, Mohan Li, Chenyan Liu, Xinyu Weng, Li Shen, Xiaochun Zhang, Hao Lu, Aijun Sun & Junbo Ge

  4. Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, China

    Shuai Song, Xiaokai Zhang, Zihang Huang, Linqi Zeng, Fengze Cai, Tongyao Wang, Yining Song, Jiahao Guo, Mohan Li, Chenyan Liu, Xinyu Weng, Li Shen, Xiaochun Zhang, Hao Lu, Aijun Sun & Junbo Ge

  5. National Clinical Research Center for Interventional Medicine, Shanghai, China

    Shuai Song, Xiaokai Zhang, Zihang Huang, Linqi Zeng, Fengze Cai, Tongyao Wang, Yining Song, Jiahao Guo, Mohan Li, Chenyan Liu, Xinyu Weng, Li Shen, Xiaochun Zhang, Hao Lu, Aijun Sun & Junbo Ge

  6. Department of cardiac surgery, Zhongshan Hospital, Fudan University, Shanghai, China

    Shuyang Lu

  7. Department of Physical Education, Shanghai University of Traditional Chinese Medicine, Shanghai, China

    Ping Zhu

  8. Institutes of Biomedical Sciences, Fudan University, Shanghai, China

    Aijun Sun & Junbo Ge

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Contributions

Aijun Sun and Junbo Ge conceived and designed the study. Shuai Song, Xiaokai Zhang, Zihang Huang, Linqi Zeng, Fengze Cai, Tongyao Wang, Jiahao Guo, Mohan Li, Chenyan Liu, Yining Song, Hao Lu, Xinyu Weng, Li Shen, Xiaochun Zhang and Ping Zhu performed the experiments and analysed the data. Shuai Song and Xiaokai Zhang drafted the manuscript. Shuyang Lu provided the clinical samples. Aijun Sun and Junbo Ge provided critical revisions of important intellectual content within the manuscript and provided final approval of the version of the manuscript for publication.

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Correspondence to Hao Lu, Ping Zhu, Aijun Sun or Junbo Ge.

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Song, S., Zhang, X., Huang, Z. et al. Cardiac fibroblast Foxm1 deficiency prevents pressure overload-induced cardiac remodeling via the Usp10/MKK6-p38γ MAPK axis. Cell Death Differ (2025). https://doi.org/10.1038/s41418-025-01609-1

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