mTOR 通路通过调节 FANCD2 表达在内在化疗耐药中发挥关键作用；然而，mTOR 调节 FANCD2 表达和相关抑制剂的潜在机制尚未明确阐明。我们之前证明，小蜈蚣 (C. minima) 提取物通过抑制 FANCD2 活性发挥有希望的化学增敏作用。在此，我们的目的是鉴定 C. minima 中的生物活性化学增敏剂并阐明其潜在机制。免疫印迹、免疫荧光、流式细胞术、彗星测定、siRNA 转染和动物模型。采用在线SynergyFinder软件测定ArC与化疗药物对NSCLC细胞的协同作用。本研究发现ArC与顺铂（CDDP）、丝裂霉素C（MMC）等DNA交联药物具有协同细胞毒作用在非小细胞肺癌细胞中。 ArC 处理显着降低 NSCLC 细胞中 FANCD2 的表达，从而减弱 CDDP 诱导的 FANCD2 核灶形成，导致 DNA 损伤和细胞凋亡。此外，ArC 抑制 mTOR 通路并显着减弱 mTOR 介导的 E2F1（FANCD2 的关键转录因子）的表达。此外，ArC 和 CDDP 的共同给药通过抑制肿瘤组织中的 mTOR/FANCD2 信号传导，在 A549 异种移植小鼠模型中发挥协同抗癌作用。这些发现表明，ArC 通过抑制 mTOR 来抑制 DNA 交联药物诱导的 DNA 损伤反应/E2F1/FANCD2 信号轴，充当化学增敏剂。这提供了对ArC抗癌机制的深入了解，并提供了一种潜在的组合抗癌治疗策略。本文受版权保护。版权所有。

The mTOR pathway plays critical roles in intrinsic chemoresistance by regulating FANCD2 expression; however, the underlying mechanisms by which mTOR regulates FANCD2 expression and related inhibitors have not been clearly elucidated. We previously demonstrated that Centipeda minima (C. minima) extracts exert promising chemosensitizing effects by inhibiting FANCD2 activity. Herein, we aimed to identify the bioactive chemosensitizer in C. minima and elucidate its underlying mechanism.The chemosensitizing effects of arnicolide C (ArC), a bioactive compound in C. minima, on non-small cell lung cancer (NSCLC) were investigated using immunoblotting, immunofluoresence, flow cytometry, the comet assay, siRNA transfection, and animal models. The online SynergyFinder software was used to determine the synergistic effects of ArC and chemotherapeutic drugs on NSCLC cells.In this study, we found that ArC had synergistic cytotoxic effects with DNA cross-linking drugs such as cisplatin (CDDP) and mitomycin C (MMC) in NSCLC cells. ArC treatment markedly decreased FANCD2 expression in NSCLC cells, thus attenuating CDDP-induced FANCD2 nuclear foci formation, leading to DNA damage and apoptosis. Furthermore, ArC inhibited the mTOR pathway and significantly attenuated mTOR-mediated expression of E2F1, a critical transcription factor of FANCD2. Moreover, co-administration of ArC and CDDP exerted a synergistic anticancer effect in a A549 xenograft mouse model by suppressing mTOR/FANCD2 signaling in tumor tissues.These findings demonstrate that ArC suppresses DNA cross-linking drug-induced DNA damage response by inhibiting the mTOR/E2F1/FANCD2 signaling axis, serving as a chemosensitizing agent. This provides insight into the anticancer mechanisms of ArC and offers a potential combinatorial anticancer therapeutic strategy.This article is protected by copyright. All rights reserved.