Wogonin induces ferroptosis in pancreatic cancer cells by inhibiting the Nrf2/GPX4 axis

Abstract

Pancreatic cancer is a common gastrointestinal tract malignancy. Currently, the therapeutic strategies for pancreatic cancers include surgery, radiotherapy, and chemotherapy; however, the surgical procedure is invasive, and the overall curative outcomes are poor. Furthermore, pancreatic cancers are usually asymptomatic during early stages and have a high degree of malignancy, along with a high rate of recurrence and metastasis, thereby increasing the risk of mortality. Studies have shown that ferroptosis regulates cell proliferation and tumour growth and reduces drug resistance. Hence, ferroptosis could play a role in preventing and treating cancers. Wogonin is a flavonoid with anticancer activity against various cancers, including pancreatic cancer. It is extracted from the root of Scutellaria baicalensis Georgi. In this study, we show that wogonin inhibits the survival and proliferation of human pancreatic cancer cell lines and induces cell death. We performed RNA-sequencing and analysed the differentially expressed gene and potential molecular mechanism to determine if wogonin reduced cell survival via ferroptosis. Our results showed that wogonin upregulates the levels of Fe2+, lipid peroxidation and superoxide and decreases the protein expression levels of ferroptosis suppressor genes, and downregulates level of glutathione in pancreatic cancer cells. In addition, ferroptosis inhibitors rescue the ferroptosis-related events induced by wogonin, thereby confirming the role of ferroptosis. A significant increase in ferroptosis-related events was observed after treatment with both wogonin and ferroptosis inducer. These results show that wogonin could significantly reduces pancreatic cancer cell proliferation and induce ferroptosis via the Nrf2/GPX4 axis. Therefore, wogonin could be potentially used for treating patients with pancreatic cancer.

Beyond Mortality: Exploring the Influence of Plant Phenolics on Modulating Ferroptosis—A Systematic Review

“…This modulation resulted in the accumulation of iron, overproduction of ROS, and cell death through ferroptosis [ 10 , 51 , 58 , 59 , 60 , 61 ]. Furthermore, amentoflavone [ 62 , 63 , 64 ], baicalin [ 54 , 55 , 65 ], erianin [ 37 , 41 , 57 , 66 , 67 ], gambogenic acid [ 68 ], auriculasin [ 69 ], wogonin [ 70 ], quercetin [ 71 , 72 ], shikonin [ 73 , 74 ], scoparone [ 75 ], osthole [ 76 ], also have shown to be able to inhibit cancer growth though the induction of ferroptosis. All of this suggests the potential for developing novel cancer treatments grounded in natural products acting as ferroptosis inducers.…”

Induction of ferroptosis by natural phenols: A promising strategy for cancer therapy

“…Liu et al have shown that by reducing NRF2 and increasing its targets (GPX4 and SLC7A11), WOG produces lipid peroxides, ROS, superoxides, excessive Fe 2+ , and also causes GSH deprivation. All of these processes lead to ferroptosis of different pancreatic cancer cell lines and decrease tumor growth in vivo and in vitro (Liu, Peng, et al, 2023).…”

“…Due to transcriptional regulation of GPX4 and SLC7A11 by NRF2, WOG can also induce ferroptosis in cancer cells.Liu et al have shown that by reducing NRF2 and increasing its targets (GPX4 and SLC7A11), WOG produces lipid peroxides, ROS, superoxides, excessive Fe 2+ , and also causes GSH deprivation. All of these processes lead to ferroptosis of different pancreatic cancer cell lines and decrease tumor growth in vivo and in vitro(Liu, Peng, et al, 2023).4.19 | 4,4 0 -Dimethoxychalcone 4,4 0 -Dimethoxychalcone (DMC) is a natural compound derived from flavonoids with antiaging properties by inducing autophagy(Carmona-Gutierrez et al, 2019). In addition, this flavonoid can induce ferroptosis in renal cell carcinoma and lung cancer cells through two mechanisms: First, DMC can upregulate NRF2 to enhance the expression of its target gene, HO-1.…”

Ferroptosis: emerging roles in lung cancer and potential implications in biological compounds

“…Further researches have shown that artemisinin and its derivatives can stimulate the ferroptosis cell pathway, containing down-regulating GPX4 expression, increasing ROS and intracellular iron production. There are some natural compounds defined as ferroptosis inducers, such as Ferroptoside ( Llabani et al, 2019 ), Erianin ( Luo and Xu, 2022 ) and Wogonin ( Liu et al, 2023a ). Ferrotocide, a diterpenoid natural product, is a thioredoxin inhibitor which inducs ferroptosis of breast cancer by inactivating thioredoxin (a cell antioxidant enzyme).…”