GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE295nnn/GSE295453/primaryOK200TranscriptomicsSus scrofaExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE295453GEOGSEfalseInterferon-induced immune signatures are associated with suppression of HEV infection in porcine cell culture modelsHepatitis E virus genotype 3 (HEV-3) is a zoonotic pathogen with pigs representing the natural host. Although HEV-3 infections in humans are often self-limiting, severe or chronic cases can occur. In contrast, HEV-3 infections in pigs, the primary reservoir, remain asymptomatic. To assess the initial transcriptional response in porcine cells during HEV-3 infection and pave the way for mechanistic studies of species-specific virus-host interactions, we aimed to establish porcine cell culture models, including primary porcine hepatocytes (PPHs) and porcine cell lines. PPHs supported the full HEV-3 replication cycle while intrinsic immunity, driven by the interferon-stimulated gene (ISG) system, played a central role in restricting viral replication. JAK-inhibition enhanced viral replication and suppressed ISG expression, highlighting the importance of IFN signaling in antiviral defense. Transcriptional profiling revealed a global modulation of host responses upon HEV infection, including pathways linked to immunity, inflammation, and metabolism. Porcine cell lines were permissive to HEV infection and treatment with recombinant porcine IFN-α subtypes induced a robust ISG response and effectively inhibited HEV replication in a dose-dependent manner. These findings establish porcine hepatocytes and cell lines as valuable tools to study HEV-host interactions, demonstrating the critical role of IFN-mediated intrinsic immunity in HEV restriction and highlighting subtype-specific antiviral effects of porcine IFN-α.2026/07/01GSE295453GSM8950381GSM8950380GSM8950379GSM8950385GSM8950374GSM8950384GSM8950373GSM8950383GSM8950372GSM8950382GSM8950378GSM8950377GSM8950387GSM8950376GSM8950386GSM895037534588295453Sus scrofa