通过SCD1介导的脂肪生成和NCOA4介导的噬铁蛋白作用,水杨甙能使三阴性乳腺癌对铁蛋白沉积敏感。

Guiqin Huang, Yawen Cai, Menghui Ren, Xiaoyu Zhang, Yu Fu, Run Cheng, Yingdi Wang, Mingxing Miao, Lingpeng Zhu, Tianhua Yan
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引用次数: 0

摘要

导言三阴性乳腺癌(TNBC)是导致女性乳腺癌死亡的主要原因。文献已证实皂苷(Sal)对治疗 TNBC 有益。然而,有关盐基 TNBC 潜在治疗靶点和机制的研究仍然有限:本研究旨在探索Sal针对TNBC的主要靶点和潜在机制:方法:整合网络药理学、生物信息学和机器学习算法策略,研究Sal在TNBC中的作用、潜在靶点和机制。实验选择了 MDA-MB-231 细胞和肿瘤裸鼠进行体外和体内实验。采用 CCK-8、LDH 试验和 Calcein-AM/PI 染色法测定细胞活力和细胞毒性。使用谷胱甘肽、谷胱甘肽过氧化物酶、丙二醛(MDA)、C11-BODIPY 581/591 探针和铁橙染料探讨了抗氧化防御、脂质过氧化和铁代谢。通过谷胱甘肽过氧化物酶4(GPX4)或硬脂酰-CoA脱饱和酶1(SCD1)过表达或核受体共激活因子4(NCOA4)缺乏来证明萨尔对TNBC的作用机制:结果:预测结果证实,在赛尔和TNBC中发现了22个铁突变相关基因,揭示了赛尔作用于TNBC的潜在机制与铁突变有关。此外,通过功能富集分析,这些基因主要参与了mTOR、PI3K/AKT和自噬信号通路。体外验证结果证实,盐通过细胞内Fe2+和脂质过氧化的升高调节铁变态反应,从而抑制TNBC细胞增殖。从机理上讲,萨尔通过抑制PI3K/AKT/mTOR轴,从而抑制SCD1介导的单不饱和脂肪酸脂质生成以诱导脂质过氧化,并促进NCOA4介导的噬铁蛋白以增加细胞内Fe2+含量,从而使TNBC细胞对嗜铁细胞增多敏感。GPX4 或 SCD1 过表达或 NCOA4 缺乏的结果进一步支持了我们的机理研究。体内实验证实,Sal对通过诱导铁变态反应来减缓肿瘤生长至关重要:总之,本研究阐明了 TNBC 的发病机制与铁氧化密切相关,并确定了 TNBC 的潜在生物标志物。同时,该研究还阐明了萨尔通过 SCD1 介导的脂肪生成和 NCOA4 介导的嗜铁蛋白,在 PI3K/AKT/mTOR 信号通路的调控下,使 TNBC 对铁蛋白沉积敏感。我们的研究结果为应用赛尔治疗 TNBC 提供了理论依据。
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Salidroside sensitizes Triple-negative breast cancer to ferroptosis by SCD1-mediated lipogenesis and NCOA4-mediated ferritinophagy.

Introduction: Triple-negative breast cancer (TNBC) is the primary cause of breast cancer-induced death in women. Literature has confirmed the benefits of Salidroside (Sal) in treating TNBC. However, the study about potential therapeutic targets and mechanisms of Sal-anchored TNBC remains limited.

Objective: This study was designed to explore the main targets and potential mechanisms of Sal against TNBC.

Methods: Network pharmacology, bioinformatics, and machine learning algorithm strategies were integrated to examine the role, potential targets, and mechanisms of the Sal act in TNBC. MDA-MB-231 cells and tumor-bearing nude mice were chosen for in vitro and in vivo experimentation. Cell viability and cytotoxicity were determined using CCK-8, LDH test, and Calcein-AM/PI staining. Antioxidant defense, lipid peroxidation, and iron metabolism were explored using glutathione, glutathione peroxidase, malondialdehyde (MDA), C11-BODIPY 581/591 probe, and FerroOrange dye. Glutathione peroxidase 4 (GPX4) or stearoyl-CoA desaturase 1 (SCD1) overexpression or nuclear receptor co-activator 4 (NCOA4) deficiency was performed to demonstrate the mechanism of Sal on TNBC.

Results: The prediction results confirmed that 22 ferroptosis-related genes were identified in Sal and TNBC, revealing that the potential mechanism of the Sal act on TNBC was linked with ferroptosis. Besides, these genes were mainly involved in the mTOR, PI3K/AKT, and autophagy signaling pathway by functional enrichment analysis. The in vitro validation results confirmed that Sal inhibited TNBC cell proliferation by modulating ferroptosis via elevation of intracellular Fe2+ and lipid peroxidation. Mechanistically, Sal sensitized TNBC cells to ferroptosis by inhibiting the PI3K/AKT/mTOR axis, thereby suppressing SCD1-mediated lipogenesis of monounsaturated fatty acids to induce lipid peroxidation, additionally facilitating NCOA4-mediated ferritinophagy to increase intracellular Fe2+ content. The GPX4 or SCD1 overexpression or NCOA4 deficiency results further supported our mechanistic studies. In vivo experimentation confirmed that Sal is vital for slowing down tumor growth by inducing ferroptosis.

Conclusions: Overall, this study elucidates TNBC pathogenesis closely linked to ferroptosis and identifies potential biomarkers in TNBC. Meanwhile, the study elucidates that Sal sensitizes TNBC to ferroptosis by SCD1-mediated lipogenesis and NCOA4-mediated ferritinophagy, regulated by PI3K/AKT/mTOR signaling pathways. Our findings provide a theoretical basis for applying Sal to treat TNBC.

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Integrated stress response activation induced by usnic acid alleviates BCL-2 inhibitor ABT-199 resistance in acute myeloid leukemia. Pharmacological upregulation of macrophage-derived itaconic acid by pubescenoside C attenuated myocardial ischemia-reperfusion injury. Population genomics analyses reveal the role of hybridization in the rapid invasion of fall armyworm. Gastrodin attenuates high fructose-induced sweet taste preference decrease by inhibiting hippocampal neural stem cell ferroptosis. Salidroside sensitizes Triple-negative breast cancer to ferroptosis by SCD1-mediated lipogenesis and NCOA4-mediated ferritinophagy.
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