What is the clinical evidence from this study?

Study design: Other. Population: Heart failure. Intervention: MYC deletion in cardiac fibroblasts or CXCR2 blockade vs. Wild-type or vehicle control. Primary outcome: Cardiac function (ejection fraction) and survival.

September 10, 2025Nature Cardiovascular Research5 citationsOpen Access

Heart failure-specific cardiac fibroblasts contribute to cardiac dysfunction via the MYC–CXCL1–CXCR2 axis

JKJin KomuroKeio University HHHisayuki HashimotoKeio University TKToshiomi KatsukiKeio University

Key Result

Deletion of MYC in cardiac fibroblasts or blockade of the CXCL1-CXCR2 axis significantly ameliorated pressure overload-induced heart failure and improved survival in mice.

Structured PICO

Does blocking the MYC-CXCL1-CXCR2 axis improve cardiac function in heart failure models?

Population

Mouse models of pressure overload-induced heart failure (transverse aortic constriction at 2 and 12 weeks), neonatal rat cardiomyocytes, human iPSC-derived cardiomyocytes, and human cardiac biopsy samples from patients with HF undergoing LVAD insertion versus controls.

Intervention

Genetic deletion or overexpression of Myc in cardiac fibroblasts, administration of neutralizing antibody against CXCR2, and shRNA-mediated knockdown of CXCL1 or CXCR2.

Comparator

Sham-operated mice, wild-type mice undergoing transverse aortic constriction, and non-failing human control hearts.

Outcome

Cardiac function (ejection fraction), survival rate, and expression of heart failure marker genes.surrogate

Identification of a heart failure-specific cardiac fibroblast subpopulation that promotes cardiac dysfunction via the MYC-CXCL1-CXCR2 pathway offers a novel therapeutic target beyond cardiomyocytes.

Limitations

Lack of high knockdown efficiency and high inter-mouse variability in AAV experiments
Need for cell-specific knockout mice to reach a clear conclusion regarding CXCR2 in cardiomyocytes
Small number of MYC-positive cardiac fibroblasts in human failing hearts
Low expression levels of MYC and CXCL1 in human samples
Small number of human samples and limited area available for sampling
Potential bias of single-nuclear RNA-seq compared to single-cell RNA-seq

Abstract

Heart failure (HF) is a growing global health issue. While most studies focus on cardiomyocytes, here we highlight the role of cardiac fibroblasts (CFs) in HF. Single-cell RNA sequencing of mouse hearts under pressure overload identified six CF subclusters, with one specific to the HF stage. This HF-specific CF population highly expresses the transcription factor Myc. Deleting Myc in CFs improves cardiac function without reducing fibrosis. MYC directly regulates the expression of the chemokine CXCL1, which is elevated in HF-specific CFs and downregulated in Myc-deficient CFs. The CXCL1 receptor, CXCR2, is expressed in cardiomyocytes, and blocking the CXCL1–CXCR2 axis mitigates HF. CXCL1 impairs contractility in neonatal rat and human iPSC-derived cardiomyocytes. Human CFs from failing hearts also express MYC and CXCL1, unlike those from controls. These findings reveal that HF-specific CFs contribute to HF via the MYC–CXCL1–CXCR2 pathway, offering a promising therapeutic target beyond cardiomyocytes. Komuro et al. identify a heart failure-specific subpopulation of cardiac fibroblasts that promotes cardiac dysfunction via the MYC–CXCL1–CXCR2 axis, highlighting a potential therapeutic target beyond cardiomyocytes.

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