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However, the molecular mechanisms underlying ORF3a\u2010mediated pathogenesis remain poorly characterized, and no therapeutic strategies targeting ORF3a currently exist. Here, we demonstrate that palmitoylation, a post\u2010translational modification, governs ORF3a\u2010mediated viral pathogenesis. Specifically, ORF3a undergoes ZDHHC18\u2010mediated palmitoylation at evolutionarily conserved Cys130\/Cys133 residues, which stabilizes the protein by masking an intrinsic proteasomal degradation signal. This palmitoylation competitively inhibits tripartite motif\u2010containing 16 (TRIM16)\u2010dependent K27\u2010linked polyubiquitination, thereby preventing ORF3a degradation and enhancing viral replication and inflammatory responses. A designed ORF3a\u2010mimicking palmitoylation\u2010inhibitory peptide (OPIP) blocked ORF3a palmitoylation, promoted its degradation, and significantly reduced SARS\u2010CoV\u20102 pathogenicity. Collectively, these findings establish ZDHHC18\u2010mediated palmitoylation as a central regulator of ORF3a stability and virulence, revealing a potentially druggable axis for disrupting SARS\u2010CoV\u20102 pathogenesis.<\/jats:p>","DOI":"10.1002\/advs.75591","type":"journal-article","created":{"date-parts":[[2026,5,10]],"date-time":"2026-05-10T18:12:47Z","timestamp":1778436767000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["ZDHHC18\u2010Mediated Palmitoylation of ORF3a Promotes SARS\u2010CoV\u20102 Pathogenesis by Antagonizing TRIM16\u2010Mediated Ubiquitination and Proteasomal Degradation"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0251-0162","authenticated-orcid":false,"given":"Sidi","family":"Yang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Respiratory Disease National Clinical Research Center for Respiratory Disease Guangzhou Institute of Respiratory Health The First Affiliated Hospital of Guangzhou Medical University  Guangzhou P. 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