Limonene-loaded nanoliposomes confer enhanced hepatoprotection against lipopolysaccharide-induced sepsis-like inflammatory liver injury via immunopharmacological modulation of Nrf2/HO-1, TLR4/NF-κB, and apoptotic signaling pathways

Sepsis is a life-threatening condition driven by dysregulated immune and inflammatory responses, leading to multi-organ dysfunction, including liver injury. This study investigated the pharmacological and toxicological effects of limonene (LM) and limonene-loaded nanoliposomes (LM-LNPs) in a lipopolysaccharide (LPS)-induced model of hepatic injury in male Albino rats. LPS caused hepatic damage marked by elevated liver enzymes, dyslipidemia, oxidative and nitrosative stress, and suppression of the Nrf2/HO-1 axis, alongside activation of TLR4/NF-κB signaling, increased cytokines, and apoptosis. Histological findings confirmed severe injury. LM treatment partially ameliorated these alterations, whereas LM-LNPs demonstrated significantly greater hepatoprotective efficacy. Specifically, LM-LNPs restored liver function biomarkers, improved lipid profiles, enhanced endogenous antioxidant defenses, and reactivated the Nrf2/HO-1 pathway, while suppressing TLR4/NF-κB-mediated inflammatory responses. This resulted in reduced cytokine production, attenuated oxidative damage, and modulation of apoptosis, with preservation of hepatic architecture. Immunohistochemical analysis further confirmed upregulation of NRF2 expression and downregulation of NF-κB in hepatic tissues. Notably, nanoliposomal encapsulation improved the pharmacokinetic and biopharmaceutical properties of limonene, including controlled release, enhanced intestinal permeability, increased systemic bioavailability, and improved hepatic tissue distribution. In conclusion, LM-LNPs exert potent hepatoprotective effects against LPS-induced sepsis-like inflammatory liver injury through coordinated modulation of oxidative stress, inflammatory signaling, and apoptosis, highlighting their potential as a nano-enabled pharmacological strategy for managing inflammation-associated liver damage. Clinical trial number Not applicable.