<p>Pathological mechanism of ferroptosis in a rat model of &#x3b1;&#x2011;naphthyl isothiocyanate&#x2011;induced chronic cholestasis</p>.

Abstract

<p>Ferroptosis is an iron&#x2011;dependent form of cell death associated with liver pathologies. However, its role in chronic cholestasis remains to be fully elucidated. The present study therefore investigated the pathological mechanism of ferroptosis in a rat model of &#x3b1;&#x2011;naphthyl isothiocyanate (ANIT)&#x2011;induced chronic cholestasis and evaluated the therapeutic potential of the iron chelator deferoxamine (DFO). Wistar rats were used to establish a chronic cholestasis model via ANIT administration, with a subset of animals receiving DFO treatment. Wistar rats that were subjected to chronic ANIT exposure were found to develop severe liver injury, characterized by impaired function, inflammation and fibrosis. In addition, pronounced iron deposition and hallmark features of ferroptosis, including elevated lipid peroxidation, depleted glutathione, and aberrant expression of acyl&#x2011;CoA synthetase long&#x2011;chain family member 4 and cyclooxygenase 2, were observed. Ultrastructural analysis revealed distinctive mitochondrial abnormalities consistent with ferroptosis. Mechanistically, these changes appeared to be mediated by suppression of the Kelch&#x2011;like ECH&#x2011;associated protein 1/nuclear factor erythroid 2&#x2011;related factor 2/heme oxygenase 1 antioxidant pathway and dysregulation of key iron metabolism proteins, including transferrin receptor 1 and ferroportin 1. Intervention with DFO markedly ameliorated the cholestatic injury, reduced iron overload and lipid peroxidation, mitigated mitochondrial damage, and normalized the expression of key proteins involved in ferroptosis, antioxidant defense and iron homeostasis. Taken together, these findings suggested that ferroptosis may be a key pathological mechanism in chronic cholestasis, driven by the concurrent disruption of antioxidant and iron metabolic capacities in hepatocytes. Therefore, targeting iron overload may be a promising therapeutic strategy for cholestasis.</p>.