ObjectHepatitis C is a contagious disease caused by infection with the hepatitis C virus (HCV) through blood and mother-to-child routes. This study intends to characterize the serum molecular features of hepatitis C using proteomics and transcriptomics.MethodsCtrl (normal population), HCV (population with previous HCV infection), and chronic HCV (patients with persistent HCV infection) groups were set up, and the expression profiles of the proteomes and transcriptomes of serum samples were identified using TMT and RNA-seq. Bioinformatics was applied to perform enrichment analysis and PPI network construction of differentially expressed proteins/genes (DEPs/DEGs). RT-qPCR and western blot verified the expression differences of DEPs/DEGs.ResultsCompared to the Ctrl group, the HCV group had 356 DEPs in serum; compared to the HCV group, the chronic HCV group had 381 DEPs in serum. DEPs are predominantly immunoglobulins and exosomal proteins that regulate carbon dioxide transport, initiation of transcription, immune responses, and bacterial and viral infections. HSPA4, HSPD1, COPS5, PSMD2 and TCP1 are key HCV-associated proteins in DEPs. The HCV group had 684 DEGs compared to the Ctrl group, and the chronic HCV group had 350 DEGs compared to the HCV group. DEGs primarily encode the extracellular matrix and regulate wound healing, cellular communication, oxidative stress, cell adhesion, viral infection, and immunity. KIF11, CENPE, TTK, CDC20 and ASPM are HCV-related hub genes in DEGs. Combined analyses revealed interactions between DEPs and DEGs, especially EIF4A3, MNAT1, and UBE2D1. Moreover, the expression patterns of EIF4A3, EIF2B1, MNAT1, SNRNP70, and UBE2D1 in DEPs/DEGs from Ctrl, HCV, and chronic HCV groups were consistent with the sequencing results.ConclusionEIF4A3, EIF2B1, MNAT1, SNRNP70, and UBE2D1 are involved in the process of HCV infection and pathogenesis, and they may be potential biomarkers for the treatment of patients with hepatitis C.