暨南大学Qi Qi等研究人员合作发现，黄芩素通过阻断JAK2/STAT3/GPX4轴引发结直肠癌细胞的铁死亡。相关论文于2024年4月29日在线发表在《中国药理学报》杂志上。

研究人员探讨了黄芩素是否能诱导结直肠癌（CRC）细胞的铁死亡。研究人员发现黄芩素（1-64μM）剂量依赖性地抑制了人类CRC株HCT116和DLD1的活力。与铁死亡抑制剂liproxstatin-1（1μM）联合处理可显著缓解黄芩素诱导的CRC细胞死亡，而自噬抑制剂氯喹（25μM）、坏死抑制剂necrostatin-1（10μM）或泛天冬酶抑制剂Z-VAD-FMK（10μM）不能挽救黄芩素诱导的CRC细胞死亡。RNA-seq分析证实，黄芩素对CRC细胞的抑制作用与铁死亡诱导有关。

研究人员发现，黄芩素（7.5-30μM）通过与JAK2直接相互作用，阻断Janus kinase 2（JAK2）/STAT3信号通路，最终导致CRC细胞中的铁死亡，从而剂量依赖性地降低HCT116和DLD1细胞中铁死亡关键调控因子GPX4的表达水平。在CRC异种移植小鼠模型中，服用黄芩素（10、20mg/kg，每两天一次，连续两周）可通过抑制肿瘤组织中的JAK2/STAT3/GPX4轴，剂量依赖性地抑制肿瘤生长，并诱导显著的铁死亡。

这项研究表明，黄芩素通过阻断JAK2/STAT3/GPX4信号通路诱导铁死亡，从而促进了黄芩素诱导的抗CRC活性，这为黄芩素在CRC治疗中的应用提供了证据。

研究人员表示，CRC是一种常见的胃肠道恶性肿瘤，化疗耐药性和副作用是其面临的挑战。治疗CRC迫切需要有效且低毒的药物。铁死亡是一种新型的细胞死亡模式，因其对癌症的治疗潜力而备受关注。黄芩素（5，6，7-三羟基黄酮）是从黄芩的干燥根中提取的主要黄酮，对包括CRC在内的多种恶性肿瘤具有抗癌作用。

附：英文原文

Title: Baicalein triggers ferroptosis in colorectal cancer cells via blocking the JAK2/STAT3/GPX4 axis

Author: Lai, Jian-qin, Zhao, Le-le, Hong, Chao, Zou, Qiu-ming, Su, Jin-xuan, Li, Si-jia, Zhou, Xiao-feng, Li, Zi-sheng, Deng, Bo, Cao, Jie, Qi, Qi

Issue&Volume: 2024-04-29

Abstract: Colorectal cancer (CRC) is a prevalent form of gastrointestinal malignancy with challenges in chemotherapy resistance and side effects. Effective and low toxic drugs for CRC treatment are urgently needed. Ferroptosis is a novel mode of cell death, which has garnered attention for its therapeutic potential against cancer. Baicalein (5, 6, 7-trihydroxyflavone) is the primary flavone extracted from the dried roots of Scutellaria baicalensis that exhibits anticancer effects against several malignancies including CRC. In this study, we investigated whether baicalein induced ferroptosis in CRC cells. We showed that baicalein (1–64μM) dose-dependently inhibited the viability of human CRC lines HCT116 and DLD1. Co-treatment with the ferroptosis inhibitor liproxstatin-1 (1μM) significantly mitigated baicalein-induced CRC cell death, whereas autophagy inhibitor chloroquine (25μM), necroptosis inhibitor necrostatin-1 (10μM), or pan-caspase inhibitor Z-VAD-FMK (10μM) did not rescue baicalein-induced CRC cell death. RNA-seq analysis confirmed that the inhibitory effect of baicalein on CRC cells is associated with ferroptosis induction. We revealed that baicalein (7.5–30μM) dose-dependently decreased the expression levels of GPX4, key regulator of ferroptosis, in HCT116 and DLD1 cells by blocking janus kinase 2 (JAK2)/STAT3 signaling pathway via direct interaction with JAK2, ultimately leading to ferroptosis in CRC cells. In a CRC xenograft mouse model, administration of baicalein (10, 20mg/kg, i.g., every two days for two weeks) dose-dependently inhibited the tumor growth with significant ferroptosis induced by inhibiting the JAK2/STAT3/GPX4 axis in tumor tissue. This study demonstrates that ferroptosis contributes to baicalein-induced anti-CRC activity through blockade of the JAK2/STAT3/GPX4 signaling pathway, which provides evidence for the therapeutic application of baicalein against CRC.

DOI: 10.1038/s41401-024-01258-z

Source: https://www.nature.com/articles/s41401-024-01258-z