探索Sappanone a在癌症中诱导铁铁诱导的机制：对由NRF2/XCT/GPX4轴介导的线粒体功能障碍的见解

非小细胞肺癌（NSCLC）是肺癌的主要亚型，包括鳞状细胞癌，腺癌和大细胞癌。与小细胞肺癌相比，NSCLC细胞生长和分裂得更慢，并且它们的转移发生在后期。目前，化学疗法是该疾病的主要治疗方法。 Sappanone A（SA）是一种从凯撒皮植物萨彭（Caesalpinia Sappan）提取的类黄酮化合物，以抗肿瘤，氧化还原调节和抗炎特性而闻名。最近的研究研究了SA与线粒体途径在通过NRF-2/GPX-4/XCT轴调节细胞死亡方面的相互作用。这项研究专门探讨了SA通过调节肿瘤细胞中线粒体和线粒体生物发生来影响线粒体形态和结构的机制。该研究主要利用第二代转录组测序数据和分子对接技术来阐明SA在调节肿瘤细胞中编程细胞死亡中的作用。 OMICS结果表明，SA处理显着靶向涉及氧化磷酸化，线粒体，线粒体动力学和氧化应激的基因。进一步的发现证实，NRF-2/GPX4/XCT途径在NSCLC治疗中是SA的关键靶标。显示NRF-2（SI-NRF-2）和NRF-2过表达（AD-NRF-2）的敲低可调节SA的治疗功效至不同程度。另外，对GPX4/XCT基因的修改显着影响SA对线粒体自噬，生物发生和能量代谢的调节作用。这些调节机制可以通过caspase途径和与铁毒相关的信号传导介导。分子生物学实验表明，SA干预进一步抑制了Tyr18上基金C1的磷酸化并下调TOM20表达。发现SA处理可降低PGC1α，NRF-1和TFAM的表达，从而降低线粒体呼吸和能量代谢。 NRF-2的过表达被证明可以抵消SA对线粒体和线粒体生物发生的调节作用。共聚焦显微镜实验进一步表明，SA处理会增加线粒体碎片化，随后诱导线粒体途径介导的程序性细胞死亡。但是，NRF-2/GPX4/XCT途径的遗传修饰显着改变了SA对肿瘤细胞的调节作用。总之，SA已被确定为NSCLC的有前途的治疗剂。线粒体途径介导的细胞凋亡和铁凋亡可能代表调节肿瘤细胞死亡的关键机制。靶向NRF-2/GPX-4/XCT轴提供了一种新型的治疗方法，可在细胞微环境中维持线粒体稳态。

Non-small cell lung cancer (NSCLC), a major subtype of lung cancer, encompasses squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. Compared to small cell lung cancer, NSCLC cells grow and divide more slowly, and their metastasis occurs at a later stage. Currently, chemotherapy is the primary treatment for this disease. Sappanone A (SA) is a flavonoid compound extracted from the plant Caesalpinia sappan, known for its antitumor, redox-regulating, and anti-inflammatory properties. Recent studies have investigated the interaction of SA with mitochondrial pathways in regulating cell death through the Nrf-2/GPX-4/xCT axis. This study specifically explores the mechanism by which SA affects mitochondrial morphology and structure through the regulation of mitophagy and mitochondrial biogenesis in tumor cells. The study primarily utilizes second-generation transcriptomic sequencing data and molecular docking techniques to elucidate the role of SA in regulating programmed cell death in tumor cells. The omics results indicate that SA treatment significantly targets genes involved in oxidative phosphorylation, mitophagy, mitochondrial dynamics, and oxidative stress. Further findings confirmed that the Nrf-2/GPX4/xCT pathway serves as a crucial target of SA in the treatment of NSCLC. Knockdown of Nrf-2 (si-Nrf-2) and Nrf-2 overexpression (ad-Nrf-2) were shown to modulate the therapeutic efficacy of SA to varying degrees. Additionally, modifications to the GPX4/xCT genes significantly affected the regulatory effects of SA on mitochondrial autophagy, biogenesis, and energy metabolism. These regulatory mechanisms may be mediated through the caspase pathway and ferroptosis-related signaling. Molecular biology experiments have demonstrated that SA intervention further inhibits the phosphorylation of FUNDC1 at Tyr18 and downregulates TOM20 expression. SA treatment was found to reduce the expression of PGC1α, Nrf-1, and Tfam, resulting in a decrease in mitochondrial respiration and energy metabolism. Overexpression of Nrf-2 was shown to counteract the regulatory effects of SA on mitophagy and mitochondrial biogenesis. Confocal microscopy experiments further revealed that SA treatment increases mitochondrial fragmentation, subsequently inducing mitochondrial pathway-mediated programmed cell death. However, genetic modification of the Nrf-2/GPX4/xCT pathway significantly altered the regulatory effects of SA on tumor cells. In conclusion, SA has been identified as a promising therapeutic agent for NSCLC. The mitochondrial pathway-mediated apoptosis and ferroptosis may represent key mechanisms in regulating tumor cell death. Targeting the Nrf-2/GPX-4/xCT axis offers a novel therapeutic approach for maintaining mitochondrial homeostasis within the cellular microenvironment.