ABSTRACT: This study focuses on lung injury and related protein changes caused by feline calicivirus (FCV) infection, aiming to provide a theoretical basis for the diagnosis, treatment, and prognosis evaluation of FCV infection. First, we investigated the geographical distribution of 69 FCV strains from different countries in the NCBI database between 2020 and 2025, and found that China had a more severe infection situation. For the FCV-BJ616 and FCV-BJDX40 strains preserved in the laboratory, immunofluorescence showed that both strains could infect F81 cells, and HE staining revealed that they could induce strong pathological changes in feline lung tissue. Proteins were extracted from cat serum samples before and after infection for differential interaction analysis (DIA). Through quality control measures including correlation coefficient calculation, principal component analysis, and heat map visualization, the serum data demonstrated high quality and reproducibility. Differential protein expression and interaction analysis were conducted on serum samples from FCV-BJ616 and FCV-BJDX40 infections, revealing the number, overlap, and specificity of upregulated and downregulated proteins between the two groups, thereby identifying potential biological functional modules and protein interaction relationships. Further GO and KEGG enrichment analyses revealed significant differences between the datasets in multiple critical biological processes and signaling pathways. DEP analysis of candidate biomarkers identified significant upregulation of ACSL4 and ACSL5 in both serum groups, potentially associated with ferroptosis-induced lung damage, while S100A2 showed significant downregulation, suggesting its potential as a prognostic biomarker for FCV. Western blotting validation confirmed consistent expression patterns of ACSL4, ACSL5, and S100A2 with FCV, indicating that ACSL4 and ACSL5 may serve as potential serum biomarkers for FCV, while S100A2 could be utilized for FCV prognosis assessment.