Pteris wallichiana bioactives induce ferroptosis via the SLC7A11-GSH-GPX4 axis to directly suppress colorectal cancer.

[BACKGROUND] Colorectal cancer (CRC) is the second most lethal form of cancer and the third most prevalent malignancy worldwide. Surgery, chemotherapy, and targeted therapy have been extensively utilized in the treatment of CRC. However, some patients still develop resistance to these treatments. Ferroptosis is a recently discovered form of cell death that is distinct from more familiar nonapoptotic processes. Iron-dependent nonapoptotic cell death is characterised by the accumulation of lipid reactive oxygen species. It has been hypothesized that this process may contribute to the reversal of resistance to anticancer drugs. Pteris wallichiana is widely used medicinal resource, however, research on this topic is severely limited. Here we elucidate the chemopreventive effect and sensitize cisplatin-resistant CRC cells of Pteris wallichiana bioactives in extracts (PW-EA) and sensitize cisplatin-resistance CRC cells.

[METHODS] CRC mouse models were established by treatment with azoxymethane plus dextran sulfate sodium or SW480 and HCT116 BALB/c xenografts. These cells were treated with PW-EA (10 mg/kg and 30 mg/kg) and compared to untreated controls. RNA-seq analyses were used to determine the mode of action. Ferroptosis and mitochondrial function were determined by using flow cytometry and transmission electron microscopy. Sensitization to cisplatin was analysed in drug-resistant cells and patient-derived organoid (PDO) models. Pharmacochemical parameters and distribution were assessed using serum pharmacochemistry and liquid chromatography-mass spectrometry.

[RESULTS] PW-EA inhibited colorectal tumorigenesis in all CRC mouse models in a dose-dependent manner. Transcriptomic profiling and western blotting revealed that PW-EA inhibited SLC7A11 and glutathione peroxidase 4 (GPX4), which suppress ferroptosis. PW-EA inhibited the synthesis of the antioxidant glutathione (GSH) and resulted in increased lipid peroxidation. PW-EA significantly increased the sensitivity to cisplatin in drug resistant cell lines (SW480-cisplatin-R and HCT116- cisplatin-R) and PDO models to cisplatin. PW-EA exhibited likely low cytotoxicity and dose-proportional systemic exposure in mice. The PW-EA metabolites pterosin D glycoside and acetylpterosin C exhibited high oral bioavailability (74.2 % and 71.9 %, respectively).

[CONCLUSION] PW-EA manipulated ferroptosis via the SLC7A11-GSH-GPX4 axis to directly suppress CRC tumour cells and improve the efficacy of cisplatin chemotherapy in resistant lines. Pterosin D glycoside and acetylpterosin C were considered two of its active components. These findings provide novel perspectives and a scientific foundation for developing natural product-derived lead compounds in the treatment of colorectal cancer.