Sex-dependent cerebral inflammatory responses underlie sepsis-associated encephalopathy with altered brain oxylipin metabolism

Sepsis-associated encephalopathy (SAE) is a common complication of sepsis with significant sex dimorphism, yet the underlying mechanisms remain unclear. Oxylipin signaling plays a crucial role in neuroinflammation, but how sex modulates cerebral oxylipin profiles during sepsis has not been systematically explored. Sepsis was induced in male and female C57BL/6 mice via cecal ligation and puncture (CLP). Targeted oxylipin metabolomics of brain tissue was performed 24 h post-CLP using LC-MS/MS. Protein expression of key enzymes and transporters was analyzed by western blot and immunofluorescence; cytokines were measured by ELISA. Cognitive function was assessed by open field and novel object recognition tests at 7 days post-surgery. Sepsis induced a profound reprogramming of the cerebral oxylipin profile, characterized by cyclooxygenase (COX) pathway activation and cytochrome P450 (CYP450) epoxygenase-derived EpFA downregulation. Striking sex dimorphism was observed that male septic mice exhibited a significantly more pronounced activation of COX and lipoxygenase (LOX) pathways compared to females, accompanied by enhanced arachidonic acid/docosahexaenoic acid (AA/DHA) metabolic turnover, a trend toward lower free DHA pool, downregulation of the DHA transporter Major facilitator superfamily domain-containing protein 2 A (MFSD2A) and increased COX-2 and 12/15-LOX expression in the brain. Conversely, female septic mice preserved MFSD2A expression and showed a trend toward a larger free DHA pool compared to male septic mice. These metabolic differences were closely linked to neuropathological outcomes; male mice exhibited more severe microglial activation, neuronal loss, pro-inflammatory cytokine expression, and significant cognitive and anxiety-like behavioral deficits, from which female mice were largely protected. Sepsis induces sex-dependent remodeling of the cerebral oxylipin metabolome. The pronounced activation of COX and LOX pathways in males is a key driver of more severe neuroinflammation and cognitive impairment, while downregulation of CYP450 epoxygenase-derived EpFAs may represent a common pathological feature of SAE. These findings establish sex as a critical biological variable in SAE and identify oxylipin pathways as potential targets for sex-specific therapeutic interventions.