Sex-dependent bioactive lipid mediator profiles in multiple sclerosis.

BACKGROUND: Pathophysiological drivers of sex differences in multiple sclerosis (MS) remain unclear. Potential candidates include bioactive lipid mediators (LMs), which are pivotal regulators of neuro-inflammatory responses. OBJECTIVE: To investigate sex-dependent LM differences in MS. METHODS: Plasma lipids were measured using targeted HPLC-MS/MS in a birth-year MS cohort (N = 410; n = 285 MS, n = 169 RRMS, n = 80 SPMS and n = 36 PPMS). Lipid profiles were compared between sexes and correlated with disability (Expanded Disability Status Scale (EDSS)), neuroaxonal damage (neurofilament light, NfL), whole brain volume (WBV) and T2 lesion volume (LV). RESULTS: In healthy controls, 9-HOTrE levels were higher in women than men. In individuals with MS, women had higher 9-HOTrE, 18-HEPE and 9-HODE levels than men, while men had higher 15-HEPE, 17-HDHA and 11,12-DiHET levels than women. Among these LMs, increased 11,12-DiHET levels were associated with higher EDSS and NfL levels, while higher levels of the remaining LMs, such as 9-HOTrE, were associated with lower EDSS and lower LV. CONCLUSION: These findings provide insights into potential sex-dependent lipid-mediated pathophysiological mechanisms in MS patients. Our findings suggest that certain LMs, such as 9-HOTrE, may display neuroprotective effects in MS.