Polydatin ameliorates ovalbumin-induced asthma in a rat model through NCOA4-mediated ferroautophagy and ferroptosis pathway.

Asthma is one of the most prevalent chronic diseases worldwide. In this study, we aimed to explore whether polydatin can achieve therapeutic effects in experimental asthma in a rat model by suppressing ferroptosis and its potential mechanism of inhibiting ferroptosis. We established a rat asthma model, and five experimental groups were established: the control group, model group, polydatin group, 3-MA group, and Fer-1 group. We compared general conditions, behavioral changes, Fe(3+)deposition, pathological changes, pulmonary function, serum IgE levels, ferroautophagy-related genes, and ferroptosis-related genes expression among the groups. Following the polydatin intervention, the mental state of the rats stabilized, their fur condition improved, and both food intake and body weight increased. The incubation period of asthma lengthened, and they sneezed and scratched less frequently. Additionally, polydatin reduced serum IgE levels and Fe(3+) deposition, enhanced lung function and pathological alterations, and also downregulated the expression of nuclear receptor coactivator 4 (NCOA4), Bcl-2 homologous domain protein (Beclin1), Fe(2+), malondialdehyde (MDA), and 4-hydroxynonenal (4-HNE) in lung tissue. Levels of ferritin heavy chain 1 (FTH1), ubiquitin-binding protein p62 (P62), glutathione (GSH), glutathione peroxidase 4 (GPX4), and solute carrier family 7 member 11 (SLC7A11) were all upregulated. In conclusion, in this rat model, polydatin was capable of reducing Fe(2+) overload by inhibiting the NCOA4-mediated ferroautophagy. This, in turn, inhibited ferroptosis in the lung tissues, thereby alleviating asthma symptoms. Further studies, including clinical trials, are required to validate this result.