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 (489 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 (n = 3 mice/group): 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 DNA/RNA-binding and antioxidant activities, and liver-specific enrichment in growth factor receptor signaling and kinase regulation. STRING networks showed a kidney-specific interaction cluster centered on Sod2, Sirt3, and Jun, whereas liver showed only a discrete Egfr–Gstp1 pair. Notably, aging-annotated DEPs functioned as network hubs, directly connecting to approximately 50% of non-aging-annotated 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.