黄芩通过 KEAP1-NRF2/HO-1 通路调控铁蛋白自噬和巨噬细胞免疫促进非小细胞肺癌对顺铂的敏感性。
Baicalin promotes the sensitivity of NSCLC to cisplatin by regulating ferritinophagy and macrophage immunity through the KEAP1-NRF2/HO-1 pathway.
机构信息
Department of Respiratory and Critical Care Medicine, Changzheng Hospital, Naval Medical University, Shanghai, 200003, China.
出版信息
Eur J Med Res. 2024 Jul 26;29(1):387. doi: 10.1186/s40001-024-01930-4.
BACKGROUND
Cisplatin (DDP) chemotherapy is commonly used in therapy for non-small cell lung cancer (NSCLC), but increased drug resistance has become a huge obstacle. Baicalin (BA) contributed to the sensitivity of NSCLC to DDP. Here, we aimed to further probe the pathophysiological mechanisms of BA in NSCLC.
METHODS
A549 and A549/DDP cells and xenograft mice were treated with BA and DDP. Xenograft mice were treated additionally with the NRF2 inducer (Bardoxolone methyl, BM) and KEAP1 knockdown. The levels of ferritinophagy-related proteins and biomarkers were determined. The autophagosomes were observed. M1 macrophage polarization and the contents of related indicators were analyzed. The involvement of KEAP1/NRF2/HO-1 was determined.
RESULTS
BA inhibited cell development, and the effect of BA and DDP on cell development was additive. The abundance of ferritinophagy-related proteins and the number of autophagosomes were induced by BA. BA also promoted the transition of GSH to GSSH. BA favored M1 macrophage polarization and affected the expression of related proteins. When BA and DDP combined, these molecular phenomena were further exacerbated. BA induced accumulation of KEAP1 and reduction of NRF2 and HO-1. However, BM and KEAP1 knockdown disrupted the synergistic effects of BA and DDP on inhibiting NSCLC growth. BM and KEAP1 knockdown reversed DDP and BA-promoted protein expression activity and M1 macrophage polarization.
CONCLUSION
Our findings suggest that BA is involved in ferritinophagy and macrophage immunity through the KEAP1-NRF2/HO-1 axis, thereby improving the DDP sensitivity in NSCLC, which could provide new candidates for treatment strategies.
背景
顺铂（DDP）化疗常用于非小细胞肺癌（NSCLC）的治疗，但耐药性增加已成为巨大障碍。黄芩苷（BA）可提高 NSCLC 对 DDP 的敏感性。本研究旨在进一步探讨 BA 对 NSCLC 的病理生理机制。
方法
用 BA 和 DDP 处理 A549 和 A549/DDP 细胞及异种移植瘤小鼠。用 NRF2 诱导剂（Bardoxolone methyl，BM）和 KEAP1 敲低处理异种移植瘤小鼠。测定铁蛋白自噬相关蛋白和生物标志物的水平。观察自噬体。分析 M1 巨噬细胞极化和相关指标的含量。确定 KEAP1/NRF2/HO-1 的参与情况。
结果
BA 抑制细胞生长，BA 和 DDP 对细胞生长的作用具有加性。BA 诱导铁蛋白自噬相关蛋白丰度增加和自噬体数量增加。BA 还促进 GSH 向 GSSH 的转化。BA 有利于 M1 巨噬细胞极化并影响相关蛋白的表达。当 BA 和 DDP 联合使用时，这些分子现象进一步加剧。BA 诱导 KEAP1 积累，减少 NRF2 和 HO-1。然而，BM 和 KEAP1 敲低破坏了 BA 和 DDP 抑制 NSCLC 生长的协同作用。BM 和 KEAP1 敲低逆转了 DDP 和 BA 促进的蛋白表达活性和 M1 巨噬细胞极化。
结论
本研究结果表明，BA 通过 KEAP1-NRF2/HO-1 轴参与铁蛋白自噬和巨噬细胞免疫，从而提高 NSCLC 对 DDP 的敏感性，可为治疗策略提供新的候选药物。
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