Mitigation of Fe3O4 Nanoparticle-Induced Hepatotoxicity via Green Synthesis and CMC-Coating: An Integrated Experimental and Computational Study of Catechin-Mediated Antioxidant Pathways

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Iron oxide (Fe3O4) nanoparticles show great clinical promise, yet translational progress is often hindered by hepatic stress. Here, we evaluated the hepatic compatibility of chemically synthesized, green-synthesized, and chitosan-coated green Fe3O4 nanoparticles (50–150 mg/kg) in Wistar rats. Green synthesis yielded larger hydrodynamic diameters (21.51±1.7 nm) and more negative zeta potentials (−25.0±0.87 mV) than chemical routes (13.19±1.2 nm; −19.0±0.34 mV). Uncoated formulations induced marked liver injury, characterized by elevated serum transaminases and extensive parenchymal disruption (histological score: 13.4±1.4). Chitosan coating significantly mitigated tissue lesions (score: 3.3±1.2, p<0.001) and normalized non-enzymatic total antioxidant capacity (252.52±53.71 U/mg protein) and glutathione peroxidase activity to control levels; however, recovery was parameter-specific, as serum transaminases were attenuated but remained moderately above baseline. Hepatic gene expression revealed notable downregulation of Gsr (0.12–0.36-fold) and Smad4 (0.24–0.52-fold), marked induction of Mt1 (up to 5.00-fold), and preserved Akt1 levels in coated groups. Triplicate 200-ns molecular dynamics simulations supported a structural hypothesis in which epigallocatechin gallate stably occupies the Akt1 binding cleft (ΔGbind=−3.03±5.19 kcal/mol) without inducing dynamic denaturation. Combining green synthesis with chitosan functionalization effectively shields against microvascular injury and antioxidant exhaustion while attenuating hepatocellular leakage. Although computationally predicted target interactions require future biophysical validation, this surface-engineering approach provides a viable translational framework for mitigating inorganic nanoparticle hepatotoxicity.