Astragaloside IV regulates the ferroptosis signaling pathway via the Nrf2/SLC7A11/GPX4 axis to inhibit PM2.5-mediated lung injury in mice

Wang, Xiaoming; Wang, Yilan; Huang, Demei; Shi, Shihua; Pei, Caixia; Wu, Yongcan; Shen, Zherui; Wang, Fei; Wang, Zhenxing

doi:10.1016/j.intimp.2022.109186

Cited by 66 publications

(23 citation statements)

References 58 publications

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“…Our study highlighted a decrease in GPX4 expression, along with downregulation of cystine/glutamate antiporter SLC7A11 and ferritin heavy chain FTH1 in OGD/R‐exposed RPE cells. Conversely, ACSL4, a key player in iron‐dependent oxidative stress and vital for converting long‐chain fatty acids to acyl‐coenzymes, exhibited heightened expression 22,25 . Intriguingly, inhibiting or silencing PLD1 and PLD2 boosted GPX4, SLC7A11, and FTH1 expression while reducing ACSL4 levels, underscoring their potential roles in ferroptosis regulation through interactions with these pivotal players.…”

Section: Discussionmentioning

confidence: 97%

“…Additionally, iron overload resulting from I/R injury can contribute to the induction of ferroptosis. Excessive cellular iron levels can lead to ROS production via the Fenton reaction, resulting in further oxidative damage and lipid peroxidation 24–26 . Overall, the interplay between oxidative stress, iron overload, and lipid peroxidation contributes to the development of ferroptosis and exacerbates I/R injury‐induced tissue damage.…”

Section: Introductionmentioning

confidence: 99%

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OGD/R‐induced ferroptosis and pyroptosis in retinal pigment epithelium cells: Role of PLD1 and PLD2 modulation

Park,

Kang,

Park

et al. 2023

Cell Biochemistry & Function

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This study investigated the role of phospholipase D (PLD) in retinal ischemia–reperfusion (I/R) injury using an oxygen‐glucose deprivation/reperfusion (OGD/R) model commonly used in retinal I/R injury research. To create an in vitro cellular I/R model, pharmacological inhibitors and small interfering RNA (siRNA) were used to target PLD1 and PLD2 in retinal pigment epithelial (RPE) cells. Treatment with PLD inhibitors and siRNA reduced reactive oxygen species (ROS) and malondialdehyde (MDA) induced by OGD/R in RPE cells and increased the levels of superoxide dismutase (SOD) and glutathione (GSH), indicating a reduction in oxidative damage and improvement in the antioxidant system. Next, we showed that inhibiting PLD1 or PLD2 reduced intracellular iron levels and lipid peroxidation, which are critical factors in ferroptosis. Additionally, PLD1 and PLD2 modulated the expression of proteins involved in the regulation of ferroptosis, including GPX4, SLC7A11, FTH1, and ACSL4. We also investigated the roles of PLD1 and PLD2 in preventing pyroptosis, another form of programmed cell death associated with inflammation. Our study found that OGD/R significantly increased the production of pro‐inflammatory cytokines and activated caspase‐1, NLRP3, ASC, cleaved‐caspase 1 (C‐caspase‐1), and GSDMD‐N in RPE cells, indicating pyroptosis induction. However, PLD1 and PLD2 inhibition or knockdown significantly inhibited the production of pro‐inflammatory cytokines and activation of the NLRP3 inflammasome, Taken together, our findings support the hypothesis that the PLD signaling pathway plays a key role in OGD/R‐induced ferroptosis and pyroptosis induction and may be a potential therapeutic target for preventing or treating retinal dysfunction and degeneration.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

OGD/R‐induced ferroptosis and pyroptosis in retinal pigment epithelium cells: Role of PLD1 and PLD2 modulation

Park,

Kang,

Park

et al. 2023

Cell Biochemistry & Function

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“…Activation of Nrf2 target genes is known to alleviate lung injury induced by PM2.5 exposure, as indicated by reduced airway inflammation and pulmonary fibrosis, and improved immune function (Shan et al, 2022; Zhou et al, 2015). In addition, ferroptosis participates in the lung injury induced by PM2.5, and during this process, free iron plays a crucial role (Wang, Wang, et al, 2022). The excessive accumulation of iron results in the production of many free radicals, and high levels of free radicals trigger damage to DNA, proteins and other biomolecules (Chen et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Activation of Nrf2 signalling pathway by tectoridin protects against ferroptosis in particulate matter‐induced lung injury

Dong

Fan

Zheng

et al. 2023

British J Pharmacology

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Background and PurposeOur previous research showed that ferroptosis plays a crucial role in the pathophysiology of PM2.5‐induced lung injury. The present study aimed to investigate the protective role of the Nrf2 signalling pathway and its bioactive molecule tectoridin in PM2.5‐induced lung injury by regulating ferroptosis.Experimental ApproachWe examined the regulatory effect of Nrf2 on ferroptosis in PM2.5‐induced lung injury and Beas‐2b cells using Nrf2‐knockout (KO) mice and Nrf2 siRNA transfection. The effects and underlying mechanisms of tectoridin on PM2.5‐induced lung injury were evaluated in vitro and in vivo.Key ResultsNrf2 deletion increased iron accumulation and ferroptosis‐related protein expression in vivo and vitro, further exacerbating lung injury and cell death in response to PM2.5 exposure. Tectoridin activated Nrf2 target genes and ameliorated cell death caused by PM2.5. In addition, tectoridin prevented lipid peroxidation, iron accumulation and ferroptosis in vitro, but in siNrf2‐treated cells, these effects almost disappeared. In addition, tectoridin effectively mitigated PM2.5‐induced respiratory system damage, as evaluated by HE, PAS, and inflammatory factors. Tectoridin also augmented the antioxidative Nrf2 signalling pathway and prevented changes in ferroptosis‐related morphological and biochemical indicators, including MDA levels, GSH depletion and GPX4 and xCT downregulation, in PM2.5‐induced lung injury. However, the effects of tectoridin on ferroptosis and respiratory injury were almost abolished in Nrf2‐KO mice.Conclusion and ImplicationsOur data proposed the protective effect of Nrf2 activation on PM2.5‐induced lung injury by inhibiting ferroptosis‐mediated lipid peroxidation and highlight the potential of tectoridin as a PM2.5‐induced lung injury treatment.

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“…Moreover, astragaloside IV, an isolated substance from the water extract of Astragalus membranaceus, possesses anti-inflammatory, antioxidant, and immunity-boosting properties. It is conceivable for the Nrf2/SLC7A11/GPX4 signaling pathway to modulate ferroptosis [ 97 , 98 ]. Ginsenoside, the active ingredient in traditional Chinese medicine ginseng, has anticancer, antioxidant, anti-inflammatory, immunomodulatory, hypoglycemic, and antidiabetic effects.…”

Section: Effects Of Ferroptosis On Cardiovascular Diseasementioning

confidence: 99%

Effects of Ferroptosis on Cardiovascular Diseases

Zhang

et al. 2023

Mediators of Inflammation

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Ferroptosis is a novel form of programmed cell death characterized by the accumulation of iron-dependent lipid peroxides, which causes membrane injury. Under the catalysis of iron ions, cells deficient in glutathione peroxidase (GPX4) cannot preserve the balance in lipid oxidative metabolism, and the buildup of reactive oxygen species on the membrane lipids leads to cell death. An increasing body of evidence suggests that ferroptosis plays a significant role in the development and occurrence of cardiovascular diseases. In this paper, we mainly elaborated on the molecular mechanisms regulating ferroptosis and its impact on cardiovascular disease to lay the groundwork for future studies on the prophylaxis and treatment of this patient population.

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Astragaloside IV regulates the ferroptosis signaling pathway via the Nrf2/SLC7A11/GPX4 axis to inhibit PM2.5-mediated lung injury in mice

Cited by 66 publications

References 58 publications

OGD/R‐induced ferroptosis and pyroptosis in retinal pigment epithelium cells: Role of PLD1 and PLD2 modulation

OGD/R‐induced ferroptosis and pyroptosis in retinal pigment epithelium cells: Role of PLD1 and PLD2 modulation

Activation of Nrf2 signalling pathway by tectoridin protects against ferroptosis in particulate matter‐induced lung injury

Effects of Ferroptosis on Cardiovascular Diseases

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