Commentary on: Activation of Nrf2 signalling pathway by tectoridin protects against ferroptosis in particulate matter-induced lung injury

Wenfu Cao¹, Xinrui Guo¹, Xinyu Li, Dapeng Chen^1*

¹Compartive medicine, Dalian Medical University, Dalian city, 116044, Liaoning province, China.

*Corresponding author: Dapeng Chen, Comparative Medicine Department of Researching and Teaching, Dalian Medical University, Dalian 116044, P. R. China, Tel/Fax: +86 411 86110862; Email: cdp.9527@163.com.

KEYWORDS: lung injury, cell death, PM2.5, drug discovery, ferroptosis

We read with great interest the article entitled ”Activation of Nrf2 signalling pathway by tectoridin protects against ferroptosis in particulate matter-induced lung injury ” by Dong et al. in the British Journal of Pharmacology (Donget al. , 2023).

The authors demonstrate that tectoridin has a therapeutic effect on particulate matter-induced lung injury (PM2.5-induced lung injury), and they believe that, this treatment mechanism is related to the inhibition of ferroptosis through targeting Nrf2. There are varying opinions regarding the future of targeted ferroptosis inhibition in the treatment of PM2.5-induced lung injury, and its clarity remains uncertain.

With the rapid economic development, air pollution has emerged as the fifth most significant risk factor for all-cause mortality on a global scale, imposing a substantial economic burden. The animal model of lung injury, commonly employed in fundamental studies, involves the inhalation of PM2.5. In the case of lung injury induced by PM2.5, oxidative stress and inflammation, which are well-recognized indicators of lung injury, closely mirror the clinical symptoms of such injury. To induce severe and easily measurable markers of lung injury, mice were exposed to highly concentrated levels of PM2.5. Prolonged exposure to PM2.5 instigates the overproduction of reactive oxygen species (ROS), precipitating oxidative stress that results in apoptosis, and in more severe cases, necrosis (Zhao et al. , 2022).

The signaling pathways involved in PM2.5-induced lung injury encompass cell death (apoptosis, necrosis and pyroptosis), inflammation, and increased oxidative stress(He et al. , 2021). Extensive research has factually demonstrated that compounds exhibiting anti-inflammatory and antioxidant characteristics are beneficial in alleviating PM2.5-induced lung injury. It is well known that Nrf2 activation can provide relief for lung injury through anti-inflammatory, antioxidant, and anti-apoptotic effects. Based on the current findings presented in the article by Dong et al , it is challenging to prove that tectoridin-induced treatment is directly associated with ferroptosis inhibition in PM2.5-induced lung injury. In my opinion, the conclusion should state that tectoridin administration alleviated ferroptosis in PM2.5-induced lung injury, as it remains unclear whether ferroptosis is the cause or result of PM2.5-induced lung injury. I apologize if my previous wording was not entirely accurate; it was not intended as a mere play on words, but rather an attempt at precision.

Targeted inhibition of cell death, without affecting inflammation and oxidative stress, has never proven to be a satisfactory option for alleviating tissue injury. In PM2.5-induced lung injury, apoptosis is the primary form of cell death and is typically a direct consequence of excessive oxidative stress following PM2.5 exposure . However, the direct inhibition of apoptosis using caspase inhibitors has some palliative effects and is not an ideal treatment (Liu et al. , 2016).

Ferroptosis, on the other hand, is a form of regulated cell death triggered by lipid peroxidation. Unlike apoptosis, it does not follow the typical apoptotic pathway and possesses immunogenic properties. The classic biochemical marker of ferroptosis is GPX4, SLC7A11, ATP5G3, and NOCA4. Metabolic disruptions in lipids, iron, and amino acids are closely associated with the activation of ferroptosis. Therefore, in this discussion, we will carefully explore the effectiveness of targeted ferroptosis inhibition in alleviating PM2.5-induced lung injury.

Firstly, there is still a lack of large-scale clinical research to provide evidence for the causal relationship between ferroptosis and PM2.5-induced lung injury. Many current conclusions are obtained from animal or cell studies. While apoptosis and necrosis are the predominant cell death types in PM2.5-induced lung injury, recent studies have also reported other types of cell death, including necroptosis and ferroptosis. The association between ferroptosis and PM2.5-induced lung injury has only recently been observed, and further investigation is needed to establish the definitive causality. There are suggestions that PM2.5 may play a role in inducing death of lung epithelial cells through its influence on the balance of iron overload, lipid peroxidation, and redox reactions. However, whether ferroptosis is the main cause and promise target of PM2.5 induced lung injury requires further study. A search conducted on PubMed using the keywords ”PM2.5; acute lung injury; ferroptosis” yielded approximately 13 publications between 2021 and 2024. Unfortunately, none of these studies provide conclusive evidence supporting ferroptosis as the primary pathological mechanism or promise target of PM2.5-induced lung injury. The lack of precise and convincing experimental designs and results undermines the conclusion that inhibiting ferroptosis contributes to the alleviation of PM2.5-induced lung injury.

Secondly, the utilization of solely biochemical markers of ferroptosis to ascertain the presence or participation of ferroptosis is subject to debate, as autophagy, apoptosis, and oxidative stress exhibit overlapping characteristics with ferroptosis, potentially leading to a pseudo-manifestation of ferroptosis caused by other factors. Given these considerations, conducting a comprehensive study on the essence of ferroptosis in PM2.5 induced lung injury without the involvement of additional factors becomes a challenging endeavor.

Lastly, caution must be exercised when utilizing ferroptosis inhibitors due to the potential interference with the pharmacological properties of other drugs, thereby compromising the treatment objective. Studies have shown that combining anti-cancer drugs with a ferroptosis inducer enhances its anticancer efficacy. This discovery introduces a promising approach involving the combination of anti-cancer drugs with a ferroptosis inducer for tumor treatment. However, further comprehensive investigation is necessary to evaluate the application of ferroptosis inhibitors in the treatment of tumor patients with tissue injury syndrome, such as cisplatin-induced kidney injury (CP-AKI).

Hu et al also reported the treatment effects of leonurine on cisplatin-induced acute kidney injury by inhibiting ferroptosis in BJP journal (Hu et al., 2022). It is likely that ferroptosis is not only a concomitant phenomenon but also a secondary event triggered by cisplatin exposure. Upon acute kidney occurrence, neutrophils are the first type of accumulated white blood cells in the kidneys. In comparison to apoptotic cells, ferroptotic cells exhibit higher immunogenicity and are capable of recruiting macrophages, which subsequently induce neutrophil recruitment. However, the results have shown that in CP-AKI, both parenchymal cells and immune cells, particularly macrophages and neutrophils, display significantly upregulated activity in the ferroptosis pathway(Chen et al., 2023). This non-specific activation poses challenges to develop targeted therapeutic strategies to alleviate CP-AKI through inhibiting ferroptosis.

In conclusion, the potential for the development of ferroptosis inducers in cancer therapy holds promise. However, the effectiveness of ferroptosis inhibitors in treating PM2.5 induced lung injury or other forms of acute tissue injury remains uncertain. This correspondence should not be interpreted as a negative critique of the article by Dong et al., who have astutely observed the mitigating effects of tectoridin on ferroptosis in PM2.5-induced lung injury and have provided a probable connection between Nrf2 activation and ferroptosis inhibition. Conversely, our aim in writing this correspondence is to draw greater attention from researchers towards exploring the causal relationship between ferroptosis and acute tissue injury.

AUTHOR CONTRIBUTIONS

Dapeng Chen: Conceptualization; Wenfu CAO, Xinrui Guo, and Xinyu Li: writing original draft; Dapeng Chen and Wenfu Cao: writing, review, and editing.

CONFLICT OF INTEREST STATEMENT

The authors have no conflicts of interest to declare.

ORCID

Dapeng Chen: https://orcid.org/0000-0001-9838-1646

REFERENCES

Chen Z, Li Y, Yuan Y, Lai K, Ye K, Lin Y, et al. (2023). Single-cell sequencing reveals homogeneity and heterogeneity of the cytopathological mechanisms in different etiology-induced AKI. Cell Death Dis 14 (5):318.

Dong T, Fan X, Zheng N, Yan K, Hou T, Peng L, et al. (2023). Activation of Nrf2 signalling pathway by tectoridin protects against ferroptosis in particulate matter-induced lung injury. Br J Pharmacol 180 (19): 2532-2549.

Hu J, Gu W, Ma N, Fan X, Ci X (2022). Leonurine alleviates ferroptosis in cisplatin-induced acute kidney injury by activating the Nrf2 signalling pathway. Br J Pharmacol179 (15): 3991-4009.

Liu M, Shi L, Zou X, Zheng X, Zhang F, Ding X, et al. (2016). Caspase inhibitor zVAD-fmk protects against acute pancreatitis-associated lung injury via inhibiting inflammation and apoptosis. Pancreatology16 (5): 733-738.

Zhao C, Pu W, Wazir J, Jin X, Wei L, Song S, et al. (2022). Long-term exposure to PM2.5 aggravates pulmonary fibrosis and acute lung injury by disrupting Nrf2-mediated antioxidant function. Environ Pollut 313: 120017.