Key result
Small molecules LRN9 and DF6 induce cardiomyocyte cell-cycle re-entry and ventricular growth via Wnt/β-catenin signaling.
Why the study?
Translating canonical Wnt/beta-catenin pathway activation to promote cardiomyocyte cell cycle activity is limited by off-target and functional liabilities associated with global pathway activation.
Novel Wnt potentiators LRN9 and DF6 promote cardiomyocyte proliferation without impairing contractile function in preclinical models, offering a potential therapeutic avenue for cardiac regeneration.
May enable targeted CM proliferation in vitro; leaves open in vivo cardiac regeneration potential.
Canonical Wnt/β-catenin pathway activation can promote cardiomyocyte (CM) cell cycle activity, but translation is limited by off-target and functional liabilities associated with global pathway activation. We identified two small molecules, LRN9 and DF6, which potentiate Wnt/β-catenin signaling through a non-GSK3β mechanism and induce CM cell-cycle re-entry in human iPSC-CMs. In cardiac organoids, the effects was largely restricted to CMs and were accompanied by minimal changes in contractile and relaxation parameters, in contrast to reported impairment with GSK3β inhibition. RNA-sequencing showed enrichment of DNA replication and cell-cycle pathways. In embryonic zebrafish, both compounds increased ventricular growth consistent with CM hyperplasia.
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Asenjo et al. (2026) studied this question. LRN9 and DF6 was evaluated on Cardiomyocyte cell-cycle re-entry and ventricular growth. Small molecules LRN9 and DF6 potentiated Wnt/β-catenin signaling, inducing cardiomyocyte cell-cycle re-entry in human iPSC-CMs and increasing ventricular growth in embryonic zebrafish.
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