Retinoid X receptor alpha is a spatiotemporally predominant therapeutic target for anthracycline-induced cardiotoxicity.

To uncover the genetic basis of anthracycline-induced cardiotoxicity (AIC), we recently established a genetic suppressor screening strategy in zebrafish. Here, we report the molecular and cellular nature of , a salutary modifier mutant that affects . We showed that endothelial, but not myocardial or epicardial, activation confers AIC protection. We then identified isotretinoin and bexarotene, two FDA-approved RXRA agonists, which exert cardioprotective effects. The therapeutic effects of these drugs only occur when administered during early, but not late, phase of AIC or as pretreatment. Mechanistically, these spatially- and temporally-predominant benefits of activation can be ascribed to repair of damaged endothelial cell-barrier via regulating tight-junction protein Zonula occludens-1. Together, our study provides the first in vivo genetic evidence supporting as the therapeutic target for AIC, and uncovers a previously unrecognized spatiotemporally-predominant mechanism that shall inform future translational efforts.