Deferoxamine alleviates T-2 toxin-induced articular chondrocyte ferroptosis via the Nrf2/xCT/GPX4 axis: Implications for Kashin-Beck disease pathology.

Kashin-Beck disease (KBD) is a debilitating endemic osteochondropathy. Environmental toxins, particularly T-2 toxin, and selenium deficiency are established etiological factors. This study aimed to investigate whether T-2 toxin induces ferroptosis in articular chondrocytes and explore the therapeutic potential and mechanism of the iron chelator, Deferoxamine (DFO). A total of 32 three-week-old male Sprague-Dawley rats were randomly allocated into four groups: Control, T-2 toxin (100 ng/g·BW/d), T-2 toxin + low DFO (10 mg/kg), and T-2 toxin + high DFO (100 mg/kg). After a 4-week intervention, knee joints were analyzed using micro-CT, micro-MRI, and histopathological staining (HE and Safranin O). Chondrocyte ferroptosis was assessed via mitochondrial ultrastructure observation, iron content measurement, GSH and MDA levels, and expression analysis of key ferroptosis-related markers (Nrf2, xCT, GPX4) using RT-qPCR and Western blot. T-2 toxin exposure induced severe articular cartilage degradation, accompanied by intracellular iron overload lipid peroxidation, oxidative stress and distinctive mitochondrial damage characteristic of ferroptosis. At the molecular level, T-2 toxin significantly reduced the expression of components within the Nrf2/xCT/GPX4 signaling axis. DFO co-treatment, especially at the high dose, effectively alleviated cartilage damage, normalized iron levels, and preserved mitochondrial integrity. Mechanistically, DFO dose-dependently reversed the T-2 toxin-induced downregulation of the Nrf2/xCT/GPX4 pathway, upregulating the protein and mRNA expression of these key anti-ferroptosis markers. Our findings demonstrate that T-2 toxin induces ferroptosis in articular chondrocytes, at least partially, through the suppression of the Nrf2/xCT/GPX4 axis. DFO exerts a potent chondroprotective effect by chelating iron and promoting the expression and nuclear accumulation of these signaling proteins. This study not only elucidates a novel mechanism for T-2 toxin-induced cartilage injury-a hallmark of KBD-but also identifies ferroptosis as a promising therapeutic target, with DFO representing a potential therapeutic agent.