The coronavirus disease 2019 (COVID-19) pandemic remains an international health problem caused by the recent emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As of May 2024, SARS-CoV-2 has caused more than 775 million cases and over 7 million deaths globally. Despite current vaccination programs, infections are still rapidly increasing, mainly due to the appearance and spread of new variants, variations in immunization rates, and limitations of current vaccines in preventing transmission. This underscores the need for pan-variant antivirals and treatments. The interferon (IFN) system is a critical element of the innate immune response and serves as a frontline defense against viruses. It induces a generalized antiviral state by transiently upregulating hundreds of IFN-stimulated genes (ISGs). To gain a deeper comprehension of the innate immune response to SARS-CoV-2, its connection to COVID-19 pathogenesis, and the potential therapeutic implications, this review provides a detailed overview of fundamental aspects of the diverse ISGs identified for their antiviral properties against SARS-CoV-2. It emphasizes the importance of these proteins in controlling viral replication and spread. Furthermore, we explore methodological approaches for the identification of ISGs and conduct a comparative analysis with other viruses. Deciphering the roles of ISGs and their interactions with viral pathogens can help identify novel targets for antiviral therapies and enhance our preparedness to confront current and future viral threats.
