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

Summary

Using single-cell transcriptomics and functional studies, the authors identify a heart failure–specific fibroblast state driven by MYC that secretes CXCL1, signaling via cardiomyocyte CXCR2 to depress contractility. Genetic or pharmacologic interruption of the MYC–CXCL1–CXCR2 axis improved cardiac function in preclinical models and human relevance was supported by failing-heart fibroblast profiles.

Key Findings

• Single-cell RNA-seq identified a heart failure–specific fibroblast subcluster with high MYC expression.
• MYC directly upregulates CXCL1 in fibroblasts; CXCL1 signals via cardiomyocyte CXCR2 to depress contractility.
• Genetic deletion of Myc in fibroblasts or pharmacologic blockade of CXCL1–CXCR2 improved cardiac function in pressure overload models and human relevance was confirmed in failing-heart fibroblasts.

Clinical Implications

Targeting CXCL1–CXCR2 signaling or upstream MYC programs in cardiac fibroblasts could yield anti-remodeling therapies for heart failure. Biomarkers from this axis may aid patient stratification.

Limitations

• Preclinical models; clinical efficacy and safety of targeting MYC/CXCL1–CXCR2 remain untested
• Potential off-target and systemic effects of chemokine pathway modulation

Future Directions

Develop selective inhibitors or delivery strategies targeting fibroblast-specific MYC–CXCL1 signaling; validate axis-related biomarkers and conduct early-phase trials to assess safety and remodeling impact.