【摘要】 非小细胞肺癌（non-small cell lung cancer, NSCLC）是全球范围内致死率最高的恶性肿瘤之一，表皮生长因子受体-酪氨酸激酶抑制剂（epidermal growth factor receptor-tyrosine kinase inhibitors, EGFR-TKIs）的临床应用成功革新了EGFR突变阳性NSCLC的治疗模式，可显著延长患者无进展生存期，已成为晚期肺腺癌的一线标准治疗方案。然而，获得性耐药导致的治疗失败仍是制约临床获益的核心问题，其机制呈现高度异质性。在EGFR-TKIs耐药细胞中普遍存在a氧化应激代偿o现象，氧化还原稳态通过精确调控活性氧（reactive oxygen species, ROS）的生成与清除在肿瘤细胞增殖与凋亡的平衡中起着关键作用。本综述旨在创新性构建氧化还原平衡动态调控网络影响第三代EGFR-TKIs耐药的理论框架，着重阐释ROS在EGFR依赖性和非依赖性耐药机制中的多维调控作用，并深入探讨靶向ROS动力学阈值及抗氧化系统的干预策略，不仅为克服第三代EGFR-TKIs获得性耐药开辟a代谢检查点o调控的创新路径，也为构建基于氧化还原生物标志物的动态治疗决策系统奠定分子基础，推动肿瘤治疗由单一靶向抑制迈向多维度代谢重塑的精准医学新模式。更多还原

【Abstract】 Non-small cell lung cancer(NSCLC) ranks among the most lethal malignancies worldwide. The clinical application of epidermal growth factor receptor-tyrosine kinase inhibitors(EGFR-TKIs) have successfully revolutionized the treatment paradigm for EGFR-mutant NSCLC, significantly prolonging progression-free survival and establishing EGFR-TKIs as the standard first-line therapy for advanced lung adenocarcinoma. However, acquired resistance remains a major obstacle to sustained clinical benefit, with mechanisms that are highly heterogeneous. A phenomenon of aoxidative stress compensationo is commonly observed in EGFR-TKIs-resistant cells, where in redox homeostasis, through the precise regulation of reactive oxygen species(ROS) generation and elimination, plays a pivotal role in maintaining the balance between tumor cell proliferation and apoptosis. This review aims to innovatively construct a theoretical framework describing how dynamic redox regulation influences resistance to third-generation EGFR-TKIs. It focuses on the multifaceted roles of ROS in both EGFR-dependent and EGFR-independent resistance mechanisms, and further explores therapeutic strategies that target ROS kinetic thresholds and antioxidant systems. These insights not only propose an innovative ametabolic checkpointo regulatory pathway to overcome acquired resistance to third-generation EGFR-TKIs, but also lay a molecular foundation for developing the redox biomarkerbased dynamic therapeutic decision-making systems, thereby facilitating a shi?t in NSCLC therapy from single-target inhibition toward multi-dimensional metabolic remodeling in the context of precision medicine.更多还原