Fig. 2

The role of iron metabolism in natural products—modulated ferroptosis in respiratory diseases. Iron metabolism is intimately linked with the mechanisms through which TCM modulates ferroptosis in respiratory diseases. An accumulation of a significant amounts of ferrous ions initiates the Fenton reaction, thereby enhancing lipid peroxidation, a pivotal step in inducing ferroptosis. Free iron binds with ferritin and is subsequently transported to the endosome through the transferrin receptor. Within the endosome, STEAP3 catalyzes the conversion of ferric iron into ferrous iron, which is then channeled into the labile iron pool via DMT1. The oxidation of PUFA coincides with the formation of ferrous ions. The influx of calcium ions causes mitochondrial calcium overload, leading to a substantial accumulation of ROS, the destruction of FLC, and FTH. These events culminate in the release of ferrous ions from the labile iron pools and the Fenton reaction, precipitating ferroptosis. Moreover, factors such as Nrf2, Hif-1α, HO-1, and mtTFA accentuate the increase of labile iron, while ferritophagy emerges as another pathway inducing ferroptosis. Notations: Black Arrows (↓): Indicate facilitation. Red Rough Arrows (⟂): Indicate inhibition. Green Arrows: Indicate a decrease