Further validation demonstrated that rV45 infection triggered caspase-3 cleavage and apoptosis, which facilitated viral proliferation.<h4>Conclusions</h4>Serial passaging of CVA6 in Vero cells drives coordinated molecular and phenotypic adaptation, predominantly mediated by VP1 mutations that enhance receptor KRM1 utilization and apoptosis-associated viral replication. Here, CASP3 is linked to infection.