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Here, we utilized host lung proteomic and phosphoproteomic profiling to investigate the underlying pathology caused by the variants. Lung tissues infected with wild\u2010type GD108, Delta, or Omicron BA.1 variants showed overexpression of proteins and phosphoproteins linked to the innate immune pathway, particularly in the Omicron group, with high activation of NOD\u2010receptor and RIG\u2010I like receptor signaling pathways. Protein\u2010protein interaction (PPI) analysis revealed six key proteins, including antiviral innate immune response receptor RIG\u2010I (DDX58), and five interferon\u2010related proteins (IFIT2, ISG15, MX1, STAT1, and EIF2AK2), highlighting the importance of the innate immune response in combating all three variants. Kinase prediction analysis suggested that six kinases (DAPK1, DAPK2, DAPK3, PRACK, TTK, and MAP2K2), potentially inhibited by Fostamatinib, were activated across all three variants, and might be potential drug targets, pending further verification. Omicron infection, compared to other mutants, significantly disrupted proteins related to pulmonary structural support, like integrin and collagens, and inhibited efferocytosis, reducing the host's ability to eliminate the pathogen. These findings suggest that innate immune activation and structural disruption may contribute to Omicron\u2010related pathology, potentially being useful for research into the molecular mechanisms underlying lung injury from SARS\u2010CoV\u20102 variants.<\/jats:p>","DOI":"10.1002\/jmv.70446","type":"journal-article","created":{"date-parts":[[2025,6,19]],"date-time":"2025-06-19T06:11:50Z","timestamp":1750313510000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Proteomics and Phosphoproteomics Characteristics of the Rhesus Macaque Lung Infected With Original SARS\u2010CoV\u20102, Delta, and Omicron Variants"],"prefix":"10.1002","volume":"97","author":[{"given":"XiaoYue","family":"Tang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical 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