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Sex differences in AVS progression depend on valvular interstitial cells (VICs) activating to myofibroblasts that drive aberrant extracellular matrix remodeling. To date, no treatment strategies have leveraged cellular sex differences to determine drug combinations that target VIC myofibroblast activation. Here, we harnessed IDentif.AI, an artificial intelligence (AI)\u2013derived platform, to optimize sex-biased synergistic drug combinations that may prevent and reverse VIC myofibroblast activation on hydrogel biomaterials. The results reveal that sex-specific drug response models can be used to predict sex biases in drug efficacy and combinatorial interactions. This study provides a framework for developing AVS treatments through the integration of high-throughput hydrogel cell culture platforms and AI-driven drug optimization. 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