Wnt signaling dysregulation drives Stargardt disease pathogenesis.

Stargardt disease, the most common inherited juvenile macular degeneration, is primarily caused by ABCA4 mutations, yet the cellular origin of pathology remains debated. Here, we identify a critical role for Wnt signaling dysregulation, specifically non-canonical Wnt pathway suppression, in driving retinal pigment epithelium (RPE) dysfunction as a central mechanism of disease. Using patient-derived iPSC-RPE harboring distinct ABCA4 mutations, we demonstrate that ABCA4 loss disrupts RPE hexagonal morphology, reduces pigmentation, and aberrantly activates neural retinal differentiation. Mechanistically, transcriptomic and functional analyses revealed pronounced downregulation of non-canonical Wnt signaling (e.g., Wnt5a), which correlated with epithelial disorganization and ectopic neurogenesis. Notably, while canonical Wnt activation failed to rescue these pathological defects, pharmacological stimulation of non-canonical Wnt signaling restored RPE integrity and suppressed neural transdifferentiation in a mutation-dependent manner. These findings not only redefine ABCA4 as a regulator of epithelial Wnt crosstalk but also unveil a divergence in Wnt pathway vulnerability among patients. Our work positions non-canonical Wnt agonism as a therapeutic strategy for Stargardt and underscores the broader imperative for mutation-tailored interventions in inherited retinal diseases. By revealing phenotypic convergence on Wnt signaling dysregulation in ABCA4-deficient RPE, this study provides a framework for understanding epithelial-pathway-driven degeneration, with implications for AMD, fibrosis, and developmental disorders characterized by polarity loss.