Abstract: HPV is a common pathogen of skin and mucosa infectious diseases. Its occurrence and development are the result of complex regulation between HPV and host protein factors. HPV E2, as the early expression protein of HPV, is not only related to the replication and transcription of the virus, but also forms a complex protein interaction network with the host through post-translational modification and so on. In this review, we summarize the role and research advances of HPV E2 protein in HPV infection, hoping to provide reference for further exploring the mechanism of HPV infection and searching for new therapeutic targets for HPV infection.