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细胞生长和分裂较慢，转移发生较晚。目前，化疗是该病的主要治疗方法。 Sappanone A (SA) 是一种从苏木植物中提取的黄酮类化合物，以其抗肿瘤、氧化还原调节和抗炎特性而闻名。最近的研究调查了 SA 与线粒体途径通过 Nrf-2/GPX-4/xCT 轴调节细胞死亡的相互作用。本研究具体探讨SA通过调节肿瘤细胞的线粒体自噬和线粒体生物发生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在调节肿瘤细胞程序性细胞死亡中的作用。组学结果表明，SA 治疗显着针对参与氧化磷酸化、线粒体自噬、线粒体动力学和氧化应激的基因。进一步的研究结果证实，Nrf-2/GPX4/xCT通路是SA治疗NSCLC的重要靶点。 Nrf-2 (si-Nrf-2) 的敲低和 Nrf-2 过表达 (ad-Nrf-2) 被证明可以不同程度地调节 SA 的治疗效果。此外，GPX4/xCT 基因的修饰显着影响 SA 对线粒体自噬、生物发生和能量代谢的调节作用。这些调节机制可能通过半胱天冬酶途径和铁死亡相关信号传导介导。分子生物学实验表明，SA干预进一步抑制FUNDC1 Tyr18位点的磷酸化，并下调TOM20的表达。研究发现 SA 处理可减少 PGC1α、Nrf-1 和 Tfam 的表达，导致线粒体呼吸和能量代谢减少。 Nrf-2 的过度表达被证明可以抵消 SA 对线粒体自噬和线粒体生物合成的调节作用。共聚焦显微镜实验进一步表明，SA 处理会增加线粒体碎片，随后诱导线粒体途径介导的程序性细胞死亡。然而，Nrf-2/GPX4/xCT 通路的基因修饰显着改变了 SA 对肿瘤细胞的调节作用。总之，SA 已被确定为一种有前途的 NSCLC 治疗剂。线粒体途径介导的细胞凋亡和铁死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 轴为维持细胞微环境中的线粒体稳态提供了一种新颖的治疗方法。© 作者。

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.© The author(s).