Enhancing KLF15 activity in cardiomyocytes: a novel approach to prevent pathological reprogramming and fibrosis via nuclease-deficient dCas9VPR.

Summary

Using network-guided single-cell analyses, the authors identify reduced KLF15 activity as a hallmark of pathological cardiomyocytes and restore it with AAV-delivered CRISPRa (dCas9VPR). This epigenetic intervention suppresses fetal gene reprogramming, normalizes metabolism, and induces anti-fibrotic cardiomyocyte–fibroblast crosstalk partly via AZGP1, positioning KLF15 as a TGF-β–linked, druggable node.

Key Findings

• Single-cell network analysis identified reduced KLF15 transcriptional activity as a key feature of pathological cardiomyocytes.
• CRISPRa (dCas9VPR)–mediated KLF15 enhancement suppressed fetal reprogramming, restored metabolic homeostasis, and reduced profibrotic signaling.
• An anti-fibrotic, cell-nonautonomous effect was mediated via cardiomyocyte–fibroblast crosstalk involving KLF15-dependent AZGP1; KLF15 acts downstream of canonical TGF-β signaling; a compact AAV-CRISPRa system was engineered for human cardiomyocytes.

Clinical Implications

While preclinical, this establishes KLF15 as a tractable hub to reverse pathological remodeling and fibrosis; it motivates early-phase trials of cardiomyocyte-targeted CRISPRa or small-molecule KLF15 activators.

Limitations

• Preclinical models without in vivo large-animal or human efficacy/safety data
• Durability, off-target effects, and immunogenicity of AAV-CRISPRa require further study

Future Directions

Evaluate long-term efficacy/safety in large-animal heart failure models; optimize cardiomyocyte-specific delivery; explore small-molecule or RNA-based KLF15 modulation; assess combination with anti-fibrotic therapies.