Melatonin Ameliorates L-NAME-Induced Preeclampsia and Associated Hepatic Injury in Rats via NRF2/GPX4/SRXN1-Mediated Ferroptosis Suppression

Background: Ferroptosis, an iron-dependent cell death driven by lipid peroxidation, is implicated in the pathogenesis of various organ injuries. As preeclampsia threatens maternal liver health via this pathway, we investigated melatonin’s anti-ferroptotic efficacy in an L-NAME-induced rat model of preeclampsia, focusing on its mechanistic modulation. Methods: Preeclampsia was induced in timed-pregnant Wistar rats via daily subcutaneous injections of L-NAME (125 mg/kg) from gestational day (GD) 13 until delivery. Treatment groups received intraperitoneal melatonin (10 mg/kg/day) in either a short-term (STM; GD14 to delivery) or a long-term (LTM; GD14 to postpartum day 14) regimen. Evaluations were performed at 23 and 90 days postpartum (PPD23 and PPD90). Systolic blood pressure and 24-hour urinary protein excretion were quantified. Hepatic oxidative stress status was evaluated by measuring malondialdehyde (MDA) concentration alongside the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx). Hepatic gene expression of ferroptosis-related mediators was analyzed, including nuclear factor erythroid 2-related factor 2 (NRF2), solute carrier family 7 member 11 (SLC7A11), sulfiredoxin-1 (SRXN1), and glutathione peroxidase 4 (GPX4). A comprehensive histopathological examination of liver tissue was also performed. Results: Melatonin treatment (STM and LTM) significantly attenuated L-NAME-induced hypertension and proteinuria at all time points (P<0.001). It suppressed hepatic oxidative stress, normalizing MDA levels (LTM at PPD90) and elevating SOD/GPx activities (P<0.01). Mechanistically, melatonin reversed the downregulation of ferroptosis-related genes (NRF2, SLC7A11, GPX4; P<0.001), with STM also upregulating SRXN1 at PPD23. LTM showed superior NRF2/GPX4 induction to STM at PPD90. Both melatonin regimens mitigated L-NAME-induced persistent hepatic damage, including ductular reactions and fibrosis. Conclusion: This study demonstrates that melatonin exerts sustained protection against preeclampsia-induced hepatic injury by suppressing ferroptosis through the NRF2/GPX4/SRXN1 pathway. The treatment attenuated ductular reactions and restored redox balance.