Cytochrome P450-derived arachidonic acid metabolites as emerging therapeutic targets in menopause-associated cardiac hypertrophy.

Menopause is associated with a marked increase in cardiac hypertrophy and progression to heart failure with preserved ejection fraction (HFpEF), a condition that disproportionately affects women and lacks effective targeted therapies. Although estrogen deficiency has long been implicated in postmenopausal cardiac remodeling, emerging evidence highlights a critical role for cytochrome P450 (CYP)-derived arachidonic acid metabolites as central regulators of myocardial structure and function. In a healthy premenopausal heart, a balance between cardioprotective epoxyeicosatrienoic acids (EETs), produced by the CYP2J2 and CYP2C enzymes, and the pro-hypertrophic metabolite 20-hydroxyeicosatetraenoic acid (20-HETE), produced by the CYP4A and CYP4F isoforms, supports adaptive remodeling and diastolic function. Menopause disrupts this equilibrium by estrogen-mediated reprogramming of CYP expression and activity, leading to diminished EET bioavailability, heightened 20-HETE signaling, and accelerated EETs breakdown by soluble epoxide hydrolase (sEH). This metabolic shift induces oxidative stress, calcium imbalance, fibroblast activation, extracellular matrix buildup, and cardiomyocyte enlargement, which together lead to ventricular stiffness and diastolic failure. This review aims to consolidate contemporary experimental and translational evidence linking CYP-derived eicosanoids to menopause-related cardiac hypertrophy and to assess novel non-hormonal therapeutic approaches, including sEH inhibitors, stable EET analogs, and CYP4A/20-HETE inhibitors, that target these molecular pathways. Targeting CYP-derived metabolites represents a promising mechanism-based approach to prevent or reverse postmenopausal cardiac hypertrophy and to modify the natural history of HFpEF. Importantly, these non-hormonal strategies may offer a safer therapeutic alternative to hormone replacement therapy by avoiding the systemic risks associated with exogenous estrogen exposure while directly targeting disease-specific molecular pathways.