Ferroptosis mediated by aggregation of Triosephosphate isomerase 1 links cadmium exposure to pulmonary fibrosis.

Cadmium (Cd) is a toxic pollutant widely present in the environment that can enter the human body through diet and inhalation, posing a serious threat to ecosystems and human health. Cd exposure can cause toxicity in multiple organs, but the mechanism underlying Cd-induced pulmonary fibrosis remains incompletely understood. This study investigated the molecular mechanisms of Cd-induced pulmonary injury using both in vivo (porcine lung tissue) and in vitro (MLE-12 cells) experiments. The results showed that Cd exposure led to mitochondrial damage, iron deposition, decreased antioxidant capacity, and increased lipid peroxidation in lung tissue, indicating the occurrence of ferroptosis. Concurrently, Cd exposure induced the aggregation of Triosephosphate isomerase 1 (TPI1). This causes a loss of its enzymatic function, leading to glycolytic dysfunction, which in turn promoted inflammatory responses and fibrosis by regulating ferroptosis. In MLE-12 cells, both TPI1 overexpression and the use of the ferroptosis inhibitor Liproxstatin-1 (Lip-1) significantly alleviated Cd-induced ferroptosis and the expression of inflammation and fibrosis-related genes. This study reveals the critical role of TPI1 in Cd-induced pulmonary fibrosis, elucidating the mechanism by which Cd drives the fibrotic process through triggering ferroptosis. These findings provide new theoretical insights and potential therapeutic targets for preventing and treating Cd toxicity.