Aging induces the hepatic CYP4A-20-HETE axis with stage-dependent oxylipin remodeling.

Hepatic inflammaging is a prominent feature of aging, yet the timing and pathway architecture of hepatic oxylipin remodeling remain unclear. Here, we integrated liver histopathology with targeted LC-MS/MS profiling of oxylipins across 2, 12, 18, and 24 months in male Sprague-Dawley rats, and related mediator shifts to age-associated regulation of key metabolic enzymes, supported by human patterns. Aging was accompanied by progressive inflammatory infiltration and steatotic remodeling, alongside clear separation of hepatic oxylipin landscapes. By midlife (12-18 months), ω-6 outputs were enriched for arachidonic acid (AA)-linked mediators, including 8-iso-PGF₂α, tetranor-12(S)-HETE, and the CYP4A-associated ω-hydroxylation product 20-HETE, whereas selected linoleic acid (LA) epoxide/diol derivatives declined. In late aging (24 months), hepatic resolvin E1 (RvE1) decreased markedly despite preserved or increased ω-3 substrates/intermediates, coinciding with accumulation of DHA-derived oxidation products. These changes paralleled induction of Cyp4a8 and suppression of Alox15, and human data revealed partially aligned age-associated patterns in selected pathway-related markers in hepatic CYP4A11/ALOX15 expression and circulating mediators. Collectively, we define a staged hepatic oxylipin imbalance during aging, characterized by heightened CYP4A/20-HETE tone and attenuated ALOX15/RvE1-associated resolution.