Tissue & cell · 2026
Artemether induces JNK1/FOXO1/GPX4-mediated ferroptosis to suppress colorectal cancer.
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Ge Lv, Lu Hu, Zeng Boyun, Xiao Zhiyi, Lin Qiong, Xie Chunmao, Gao Zhuo, Liu Qianqian, Yu Shenglan
Аннотация
BACKGROUND: Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, necessitating novel therapeutic strategies. Ferroptosis, an iron‑dependent, lipid-peroxidation-driven form of cell death, has emerged as a potential tumor‑suppressive mechanism. Artemether, a derivative of Artemisia annua L., exhibits antitumor activity in various cancers, but its role in CRC and its link to ferroptosis remain unclear.
METHODS: Using an HCT116 xenograft model and CRC cell cultures, we evaluated artemether's effects on viability, migration, invasion, and histopathology. Inflammatory cytokines (TNF-α, IL-6, IL-1β, IL-18, IL-1, caspase-1) were measured. Ferroptosis was assessed by flow cytometry, electron microscopy, and biochemical markers (GSH, MDA, ROS). Mechanistic studies included network pharmacology, molecular docking, SP600125 treatment, JNK1 siRNA knockdown, ferrostatin-1 rescue, western blotting, and qRT-PCR.
RESULTS: Network pharmacology identified JNK1 as a core target of artemether in CRC. In vivo, artemether dose-dependently suppressed tumor growth, with efficacy comparable to that of oxaliplatin. In vitro, artemether inhibited CRC cell proliferation, migration, and invasion. Concurrently, artemether reduced multiple pro-inflammatory cytokines in serum and cell supernatants, indicating suppression of systemic and local inflammation. Mechanistically, artemether activated the JNK1/FOXO1/GPX4 pathway, leading to Fe²⁺ accumulation, a ROS burst, and lipid peroxidation, thereby inducing ferroptosis. These effects were reversed by the JNK inhibitor SP600125 and JNK1 knockdown. Furthermore, the ferroptosis inhibitor ferrostatin-1 significantly rescued artemether-induced cell death and lipid peroxidation, confirming ferroptosis as the primary mode of cell death.
CONCLUSION: Artemether inhibits CRC and alleviates tumor-associated inflammation by inducing JNK1/FOXO1/GPX4-mediated ferroptosis, validated pharmacologically and genetically, highlighting its potential as an immunomodulatory anticancer agent.
METHODS: Using an HCT116 xenograft model and CRC cell cultures, we evaluated artemether's effects on viability, migration, invasion, and histopathology. Inflammatory cytokines (TNF-α, IL-6, IL-1β, IL-18, IL-1, caspase-1) were measured. Ferroptosis was assessed by flow cytometry, electron microscopy, and biochemical markers (GSH, MDA, ROS). Mechanistic studies included network pharmacology, molecular docking, SP600125 treatment, JNK1 siRNA knockdown, ferrostatin-1 rescue, western blotting, and qRT-PCR.
RESULTS: Network pharmacology identified JNK1 as a core target of artemether in CRC. In vivo, artemether dose-dependently suppressed tumor growth, with efficacy comparable to that of oxaliplatin. In vitro, artemether inhibited CRC cell proliferation, migration, and invasion. Concurrently, artemether reduced multiple pro-inflammatory cytokines in serum and cell supernatants, indicating suppression of systemic and local inflammation. Mechanistically, artemether activated the JNK1/FOXO1/GPX4 pathway, leading to Fe²⁺ accumulation, a ROS burst, and lipid peroxidation, thereby inducing ferroptosis. These effects were reversed by the JNK inhibitor SP600125 and JNK1 knockdown. Furthermore, the ferroptosis inhibitor ferrostatin-1 significantly rescued artemether-induced cell death and lipid peroxidation, confirming ferroptosis as the primary mode of cell death.
CONCLUSION: Artemether inhibits CRC and alleviates tumor-associated inflammation by inducing JNK1/FOXO1/GPX4-mediated ferroptosis, validated pharmacologically and genetically, highlighting its potential as an immunomodulatory anticancer agent.