Lipid-Driven NRF2 Preconditioning Links Estrogen Deprivation to Hepatic Resilience Against Acetaminophen Injury

Background & Aims: Menopause is associated with a sustained decline in estrogen signaling that profoundly alters hepatic lipid metabolism; however, its impact on the liver response to xenobiotic stress remains poorly understood. Given that acetaminophen (APAP) overdose is a leading cause of drug-induced acute liver failure (DILI) and that sex and age influence susceptibility to hepatotoxicity, we investigated how long-term estrogen deprivation affects the development of APAP-induced liver injury (AP-ILI). Methods: Clinical data from a multicenter cohort of patients admitted following APAP overdose were analyzed to assess susceptibility to AP-ILI. To model the postmenopausal state, 12-week-old female C57BL/6JOlaHsd mice underwent bilateral ovariectomy (OVX) or sham surgery and, six months later, were challenged with acetaminophen (360 or 600 mg/kg). Mechanistic studies included NRF2 silencing, estradiol replacement, and dietary lipid modulation using a high-fat diet. Comprehensive lipidomic profiling was performed to characterize hepatic lipid remodeling, while human liver biopsies were analyzed to validate the expression of key molecular targets. Results: Women [≥]50 years of age showed a lower risk of severe AP-ILI, a phenotype recapitulated in OVX mice. Long-term estrogen deprivation induced hepatic lipid remodeling characterized by larger lipid droplets and enrichment in saturated neutral lipids, leading to sustained NRF2 activation. Enhancement of lipid remodeling with high-fat diet increased NRF2 signaling and hepatoprotection, whereas estradiol replacement reversed these effects. Consistent with these findings, women over 50 years of age exhibited increased hepatic expression of NRF2 and its target genes. Conclusions: Long-term estrogen deprivation confers protection against AP-ILI through extensive hepatic lipid remodeling, characterized by lipid droplet expansion and altered neutral lipid composition, which promotes sustained NRF2 activation.