A zebrafish stable model of Galectin-3
Galectin-3 (LGALS3/Gal-3) dysregulation has emerged as a critical mediator of inflammatory processes in arrhythmogenic cardiomyopathy (AC), playing pivotal roles in modulating Wnt/beta-catenin signaling and regulating macrophage polarization. AC is a rare genetic disorder, primarily driven by desmosomal gene variants, characterized by fibro-fatty replacement of the ventricular myocardium, progressive ventricular dysfunction, and heightened arrhythmic risk in the young and athletes. To investigate the role of this multifaceted lectin in AC pathogenesis, we developed and characterized a stable lgals3a knock-out zebrafish model. Gal-3 deficiency alone was sufficient to recapitulate hallmark AC features, including ventricular adipose infiltration, chamber dilation, pericardial effusion, and progressive arrhythmias, spanning from larval to adult stages. Ultrastructural analyses revealed disrupted desmosomes, directly implicating Gal-3 in intercellular adhesion independent of other desmosomal gene variants. Transcriptomic analyses demonstrated suppression of both Wnt/beta-catenin and TGFb signaling. Early-stage pharmacological activation of Wnt signaling partially rescued cardiac function, but structural defects persisted in adults, indicating irreversible desmosomal instability. Inflammatory profiling revealed significant immune cell infiltration and upregulation of macrophage-related proinflammatory genes (e.g., MMP12, CCL38, IL16), consistent with AC "hot phases." This study establishes Gal-3 depletion as a sufficient driver of AC-like pathology and identifies Gal-3-related pathways as promising targets for therapeutic intervention.