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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.