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Adv."],"published-print":{"date-parts":[[2026,10,16]]},"abstract":"<jats:p>\n                    <jats:italic toggle=\"yes\">Staphylococcus aureus<\/jats:italic>\n                    (SA) causes a broad range of invasive human diseases, increasingly complicated by antibiotic resistance. Macrophages (M\u03a6) play a central role in innate immunity, yet key aspects of their interaction with SA remain incompletely understood because of the pathogen\u2019s diverse immune evasion strategies. Using multi-omics and systems-level analytics, we identified the E3 ubiquitin ligase cullin 4B (CUL4B) as a host factor that modulates M\u03a6 responses to SA infection. CRISPR-mediated deletion of CUL4B in human THP-1 M\u03a6 enhanced intracellular bacterial killing, reduced cell death, decreased caspase-1 activation, and lowered interleukin-1\u03b2 production, consistent with altered inflammasome signaling. In a murine methicillin-resistant SA (MRSA) pneumonia model, CUL4B deficiency improved pulmonary bacterial clearance, reduced bacteremia, and decreased inflammatory tissue injury. Whole-lung and serum proteomics further revealed increased antimicrobial protein abundance and reduced markers of inflammatory damage. Together, these findings identify CUL4B as a regulator of M\u03a6 inflammatory responses during MRSA infection and suggest a potential host-directed pathway that could be leveraged to improve outcomes against this major pathogen.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aeh4023","type":"journal-article","created":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T17:59:24Z","timestamp":1792000764000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Integrative multi-omics reveals CUL4B as a modulator of macrophage pyroptosis and innate defense against\n                    <i>Staphylococcus aureus<\/i>"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7438-4671","authenticated-orcid":true,"given":"Fatemeh","family":"Askarian","sequence":"first","affiliation":[{"name":"Department of Pediatrics, University of California San Diego, School of Medicine, La Jolla, CA, 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