In conclusion, this study reveals that HCoV-229E enters Huh-7 cell line via clathrin-mediated endocytosis (CME), as supported by two main approaches: (i) CME-inhibitory drugs that reveal a decrease in viral entry and (ii) knock-out of AP2M1, with AP-2 being a key component in the recruitment of clathrin, and KO-cells being less susceptible to infection. Here, AP2M1 is linked to infection.