Icariin-loaded liposomal nanoparticles alleviate streptozotocin-induced diabetic hepatopathy associated with modulation of ferroptosis-related and inflammatory signaling

Diabetic hepatopathy is a major complication of type 2 diabetes mellitus characterized by metabolic dysregulation, oxidative stress, inflammation, and emerging evidence of ferroptosis-mediated liver injury. Icariin (IC), a bioactive flavonoid, exhibits hepatoprotective potential; however, its clinical applicability is limited by poor bioavailability. Liposomal nanoformulation represents a potential approach to modify IC delivery and enhance its pharmacological efficacy. Ninety rats were randomly assigned to six groups ( n = 15/group): Control, IC, IC-LNPs, NA–STZ, NA–STZ + IC, and NA–STZ + IC-LNPs. Type 2 diabetes was induced by nicotinamide (120 mg/kg, i.p.) followed 15 min later by streptozotocin (60 mg/kg, i.p.). Five days after diabetes confirmation, diabetic treatment groups received IC or IC-LNPs at an IC-equivalent dose of 80 mg/kg/day, i.p., for eight consecutive weeks. Hepatic injury was assessed through biochemical parameters, oxidative stress markers, inflammatory cytokines, ferroptosis-related markers, and histopathological and ultrastructural analyses. NA–STZ administration induced significant metabolic dysfunction, including hyperglycemia, insulin depletion, dyslipidemia, weight loss, and elevated hepatic enzyme levels. IC treatment significantly improved these parameters, while IC-LNPs produced a more pronounced protective effect. Diabetic induction was associated with reduced hepatic NRF2 and HO-1 levels, accompanied by reduced levels of GSH, SOD, CAT, and GPX, and increased oxidative stress markers (MDA and H₂O₂). IC-LNPs more effectively restored antioxidant defenses and redox homeostasis than free IC. Moreover, NA–STZ increased NF-κB and COX-2 expression and the inflammatory mediators TNF-α, IL-6, and IL-1β, which were markedly reduced by IC-LNP treatment. Importantly, diabetic hepatopathy was associated with alterations in ferroptosis-related markers, evidenced by iron accumulation (Fe²⁺), upregulation of ACSL4 and TFR1, and downregulation of GPX4 and SLC7A11. IC-LNPs significantly attenuated these alterations, consistent with modulation of ferroptosis-related processes. Histopathological and ultrastructural analyses confirmed severe hepatic damage in diabetic rats, whereas IC-LNPs markedly preserved hepatic architecture. IC-LNPs provided greater protection than free IC against NA–STZ-induced diabetic hepatopathy, associated with attenuation of oxidative stress and inflammation and modulation of NRF2/HO-1, NF-κB/COX-2, and ferroptosis-related markers. These findings support the potential of liposomal IC as a preclinical approach for diabetic liver injury; however, pharmacokinetic, biodistribution, safety, and further mechanistic studies are required before its therapeutic or translational potential can be established.