Realgar‑induced KRAS mutation lung cancer cell death via KRAS/Raf/MAPK mediates ferroptosis

Abstract

KRAS is a biomarker for non-small cell lung cancer-targeted therapy, but there is currently no effective KRAS-targeting medication. Realgar is an impelling anticancer drug, however its significance in KRAS mutant lung cancer is uncertain. According to our findings, the IC 50 of H23 (KRAS mutant) cells is 2.99 times lower than that of H1650 (non-KRAS mutant) cells. Flow cytometry and the Hoechst 33258 staining assay revealed that H1650 cells treated with 4 µg/ml realgar had an apoptotic rate of 8.2%, while H23 cells had a rate of 21.46%. Accordingly, realgar was more sensitive to KRAS mutant cells. Transcriptome sequencing test indicated that there were 481 different expression genes in H23 cells treated with realgar. In H23 cells treated with realgar, mitochondria shrank, inner membrane folding was disturbed, and mitochondrial membrane potential crushed. Realgar boosted intracellular Fe 2+ , reactive oxygen species, malondialdehyde and glutathione levels, which were all reversed by ferroptosis inhibitor Fer-1. Realgar decreased phosphorylated p-Raf, p-ERK1/2 and increased p-p38 and p-JNK, whereas only p-Raf was abolished by Fer-1. Raf inhibitor Sorafenib accelerated the realgar-induced ferroptosis. On H23 cells treated with realgar, the expression of GPX4, SCL7A11 decreased while ACSL4 expression increased; this effect could also be amplified by Sorafenib. In conclusion, the present study indicated that realgar may induce ferroptosis by regulating the Raf, and hence plays a role in anti-KRAS mutant lung cancer.

Xanthine oxidase, a therapeutic target of realgar for non-small cell lung cancer

“…For example, Liu et al evaluated the cytotoxicity of realgar in 4 types of NSCLC cell lines, including H23, A549, H460 and H1650. They demonstrated that realgar could induce apoptosis and inhibit the proliferation of NSCLC cells via inducing ferroptosis by KRAS/Raf/MAPK pathway [ 36 ]. Another study revealed that realgar inhibited the viability as well as the glucose consumption of lung cancer stem cells isolated from NSCLC cells [ 37 ].…”

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

“…In the caenorhabditis elegans model, realgar, a sulfide mineral from ores, downregulates Ras expression through the Ras/MAPK signaling pathway [105]. Further studies reveal Realgar's potential to inhibit KRASmutated lung cancer cell growth by inducing ferroptosis via the Raf-mediated Ras/MAPK pathway [106], positioning it as a promising anti-cancer agent, especially for Ras mutation-targeted ferroptosis.…”

The ACSL4 Network Regulates Cell Death and Autophagy in Diseases

“…For example, in the context of focal cerebral ischemia, ACSL4 is upregulated in a microRNA (miR-347)-dependent manner, consequently promoting neuronal apoptosis [ 95 ]. Additionally, ACSL4 directly interacts with and regulates proteins involved in apoptotic signaling pathways [ 96 ]. Thus, ACSL4 has a dual role in apoptosis: it can inhibit apoptosis by promoting fatty-acid oxidation, leading to increased phospholipid synthesis and chemoresistance, and it can promote apoptosis by producing lipid-free radicals and directly regulating apoptotic signaling pathways.…”