Ibuprofen Modulates Tissue-Specific Proteomic Signatures of LPS-Induced Inflammaging in Mice

Chronic low grade inflammation ("inflammaging") is epidemiologically linked to organ specific aging, but tissue resolved proteomic evidence remains limited. In this exploratory study, we used 4D DIA proteomics to profile heart, liver, spleen, and kidney from mice given chronic LPS (0.1 µg/day i.p., 2 months) with or without ibuprofen co treatment (0.02 mg/mL in drinking water). LPS exposure was associated with the most pronounced proteome changes in kidney (488 DEPs) and liver (293), followed by spleen (170) and heart (135). Intersecting LPS associated DEPs with the Aging Atlas database isolated aging annotated proteins; within this subset, ibuprofen co treatment corresponded to opposite direction changes in a tissue dependent manner: kidney (8/13, 61.5%), liver (4/9, 44.4%), spleen (1/8, 12.5%), and heart (0/5). Functional enrichment of these oppositely regulated aging annotated proteins revealed kidney specific enrichment in glucuronosyltransferase and oxidoreductase activities, and liver specific enrichment in iron ion binding and steroid hydroxylase activity. STRING networks showed a kidney specific interaction cluster centered on Jun and Sod2, whereas liver showed only a discrete Egfr–Gstp1 pair. Notably, aging related DEPs functioned as network hubs, directly connecting to approximately 50% of non aging DEPs in liver and 43% in kidney. Collectively, these exploratory findings identify tissue specific proteomic correlates within the aging annotated protein subset—particularly in kidney and liver—generating hypotheses for future validation in larger experimental cohorts.