CRLF1 Secreted by Cardiac Fibroblasts Promotes Human Hypertrophic Cardiomyopathy.

Summary

Using human septal tissue from 269 obstructive HCM patients with cross-species validation, the authors identify CRLF1 as a fibroblast-derived paracrine driver of cardiomyocyte hypertrophy via LIFR–JAK1/2–STAT3 signaling. Circulating and myocardial CRLF1 levels were elevated, and pathway activation promoted hypertrophy across genetically heterogeneous HCM, positioning CRLF1 as a unifying, targetable mechanism.

Key Findings

• CRLF1 is predominantly secreted by activated cardiac fibroblasts in hypertrophied myocardium and circulation of HCM patients.
• CRLF1 activates LIFR–JAK1/2–STAT3 signaling to promote cardiomyocyte hypertrophy in murine and human HCM models.
• The CRLF1 pathway operates across genetically heterogeneous HCM, suggesting a unifying, targetable mechanism.

Clinical Implications

Although preclinical, CRLF1 quantification may aid future patient stratification, and therapeutics that inhibit the CRLF1–LIFR–JAK–STAT3 axis could offer disease-modifying options beyond symptom control.

Limitations

• Causality and therapeutic modulation have not been tested in clinical trials
• Details on long-term clinical outcomes linked to CRLF1 levels are not provided

Future Directions

Develop and test CRLF1/LIFR–JAK–STAT3 inhibitors or neutralizing strategies in translational models and early-phase clinical trials; assess CRLF1 as a circulating biomarker for risk stratification and treatment response.