Recent advances in the potential effects of natural products from traditional Chinese medicine against respiratory diseases targeting ferroptosis

Abstract

Respiratory diseases, marked by structural changes in the airways and lung tissues, can lead to reduced respiratory function and, in severe cases, respiratory failure. The side effects of current treatments, such as hormone therapy, drugs, and radiotherapy, highlight the need for new therapeutic strategies. Traditional Chinese Medicine (TCM) offers a promising alternative, leveraging its ability to target multiple pathways and mechanisms. Active compounds from Chinese herbs and other natural sources exhibit anti-inflammatory, antioxidant, antitumor, and immunomodulatory effects, making them valuable in preventing and treating respiratory conditions. Ferroptosis, a unique form of programmed cell death (PCD) distinct from apoptosis, necrosis, and others, has emerged as a key area of interest. However, comprehensive reviews on how natural products influence ferroptosis in respiratory diseases are lacking. This review will explore the therapeutic potential and mechanisms of natural products from TCM in modulating ferroptosis for respiratory diseases like acute lung injury (ALI), asthma, pulmonary fibrosis (PF), chronic obstructive pulmonary disease (COPD), lung ischemia-reperfusion injury (LIRI), pulmonary hypertension (PH), and lung cancer, aiming to provide new insights for research and clinical application in TCM for respiratory health.

Keywords: Ferroptosis; Mechanism; Natural products; Respiratory diseases; TCM.

Fig. 1

The role of SLC7A11-GSH-GPX4 axis in natural products—modulated ferroptosis in respiratory diseases. The modulations of ferroptosis by natural products in respiratory diseases are orchestrated through various mechanisms, prominently via GPX4-related pathways. These pathways crucially influence lipid peroxidation, an essential process in ferroptosis. Natural products up-regulate Nrf2 gene expression, stimulating its downstream target HO-1 and enhancing SLC7A11 protein expression. Consequently, GPX4 is activated either directly or indirectly, inhibiting ferroptosis. Moreover, multiple targets are involved in regulating the SLC7A11/GPX4 axis, including the activation of system Xc⁻ , which facilitates GSH synthesis and GPX4 activation to modulate ferroptosis. On the contrary, ACSL4 overexpression catalyzes the oxidation of PUFAs into lipid hydroperoxides. These hydroperoxides are then converted into non-toxic lipid alcohols through GPX4 activation. In the context of the immune response, Interleukin IL-17 hinders GPX4, leading to induced ferroptosis. Notations: Black Arrow (↓): Indicates promotion. Red Rough Arrow (⟂): Indicates inhibition. Green Arrow: Indicates a decrease. Red Arrow: Indicates a increase.

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

Fig. 3

Classification of natural products in targeting ferroptosis in respiratory conditions. Diseases including lung cancer, ALI, COPD, asthma, PF, LIRI and PH. Flavonoids, phenols, alkaloids, terpenoids, steroids, quinones, polysaccharides, polyacetylenes, glycosides, and lactones are 10 categories of natural products, each contributing to the diverse and complex array of biochemical compounds derived from nature