Soluble epoxide hydrolase inhibition restores pro-resolving lipid mediators and reduces inflammation in localized provoked vulvodynia

Localized provoked vulvodynia (LPV) is a chronic pain disorder characterized by persistent inflammation of the vulvar vestibule, a ring of tissue immediately surrounding the vaginal opening, with no effective, mechanism-based treatments. Recent findings suggest that LPV is associated with a deficiency in pro-resolving lipid mediators, namely, epoxyeicosatrienoic acids (EETs), that may impede the resolution of inflammation. Soluble epoxide hydrolase (sEH) is the enzyme responsible for metabolizing these EETs into less potent dihydroxyeicosatrienoic acids (DHETs). Inhibiting sEH therefore prolongs the ability of these lipids to exert their anti-inflammatory properties, making it a promising therapeutic approach to restore inflammation resolution in LPV. In this study, we examined sEH expression and activity in fibroblasts derived from vestibular and external vulvar biopsies of LPV patients and controls. siRNA knockdown of sEH in primary vestibular fibroblasts reduced pro-inflammatory mediator release following IL-1β stimulation. Pharmacological sEH inhibition reduced DHET levels, increased the EET/DHET ratio, and shifted the lipidomic profile toward a pro-resolving phenotype. Treatment with three different sEH inhibitors consistently reduced pro-inflammatory mediator production in LPV fibroblasts, including IL-6, IL-8, and PGE2. These findings demonstrate that elevated sEH activity contributes to the chronic inflammatory state in LPV, and that pharmacological sEH inhibition restores lipid mediator balance and suppresses inflammatory signaling, thus supporting a novel therapeutic strategy for LPV.