# Hepatoprotection by Naringin Nanoliposomes Against Nickel Toxicity Involves Antioxidant Reinforcement and Modulation of Nrf2, NF-κB, PI3K/mTOR, JAK/STAT, and Apoptotic Pathways

## TL;DR

Naringin nanoliposomes protect the liver from nickel toxicity by boosting antioxidants and regulating key biological pathways.

## Contribution

Naringin-loaded nanoliposomes show enhanced hepatoprotective effects compared to crude naringin through improved bioavailability and multi-pathway modulation.

## Key findings

- NRG-NLPs significantly reduced oxidative stress and inflammation markers in nickel-exposed rats.
- NRG-NLPs modulated Nrf2, NF-κB, PI3K/mTOR, JAK/STAT, and apoptotic pathways more effectively than naringin alone.
- NRG-NLPs reduced hepatic nickel accumulation and preserved liver structure.

## Abstract

Background/Objectives: Nickel exposure is a significant environmental and occupational risk factor associated with the onset and progression of chronic liver diseases due to its capacity to induce persistent oxidative stress, inflammation, and hepatocellular injury. This study aimed to evaluate the enhanced hepatoprotective and antioxidant/anti-inflammatory effects of naringin-loaded nanoliposomes (NRG-NLPs), a novel nanoformulation designed to improve the bioavailability of naringin, a citrus-derived flavonoid phytochemical, against nickel sulfate (NiSO4)-induced hepatotoxicity in male Wistar rats. Methods: Ninety rats were allocated into six groups (n = 15 each): control, NRG, NRG-NLPs, NiSO4, NiSO4 + NRG, and NiSO4 + NRG-NLPs. Treatments consisted of oral administration of NRG or NRG-NLPs (80 mg/kg/day) and intraperitoneal injections of NiSO4 (20 mg/kg/day) for three weeks. Endpoints included assessment of growth performance, serum biochemistry, hepatic antioxidant status, inflammatory mediators, apoptotic gene expression, nickel tissue accumulation, and histopathological and ultrastructural liver changes. Results: NiSO4 exposure induced marked hepatic injury, evidenced by reduced body weight, adverse serum biochemical profiles, increased hepatic enzymes and bilirubin, elevated oxidative damage markers (MDA, protein carbonyls), increased proinflammatory cytokines, and upregulation of HMGB1, PI3K, mTOR, JAK/STAT, and proapoptotic genes, accompanied by aberrant nickel accumulation and severe histopathological alterations. Co-treatment with NRG-NLPs significantly ameliorated biochemical and histological disturbances, restored antioxidant defense systems (SOD, CAT, GPx, GSH, Nrf2, HO-1), and modulated key pathways of inflammation (NF-κB, TNF-α, IL-6), fibrosis (TGF-β), cell survival, and apoptosis more effectively than crude naringin. NRG-NLPs also substantially reduced hepatic nickel deposition and preserved near-normal liver architecture. Conclusions: These findings demonstrate that nanoformulated naringin confers superior hepatoprotective benefits against nickel-induced liver injury through enhanced bioavailability and multi-pathway modulation, supporting its translational potential as a citrus-derived medicinal phytochemical and dietary bioactive for the prevention and therapeutic intervention of oxidative and inflammatory chronic liver disease.