Sulforaphane Activates a Lysosome-dependent Transcriptional Program to Mitigate Oxidative Stress

Oxidative stress underlies a number of pathological conditions, including cancer, neurodegeneration, and aging. Antioxidant-rich foods help maintain cellular redox homeostasis and mitigate oxidative stress, but the underlying mechanisms are not clear. For example, sulforaphane (SFN), an electrophilic compound that is enriched in cruciferous vegetables such as broccoli, is a potent inducer of cellular antioxidant responses. NFE2L2/NRF2 (nuclear factor, erythroid 2 like 2), a transcriptional factor that controls the expression of multiple detoxifying enzymes through antioxidant response elements (AREs), is a proposed target of SFN. <i>NFE2L2/NRF2</i> is a target gene of TFEB (transcription factor EB), a master regulator of autophagic and lysosomal functions, which we show here to be potently activated by SFN. SFN induces TFEB nuclear translocation via a Ca²⁺-dependent but MTOR (mechanistic target of rapamycin kinase)-independent mechanism through a moderate increase in reactive oxygen species (ROS). Activated TFEB then boosts the expression of genes required for autophagosome and lysosome biogenesis, which are known to facilitate the clearance of damaged mitochondria. Notably, TFEB activity is required for SFN-induced protection against both acute oxidant bursts and chronic oxidative stress. Hence, by simultaneously activating macroautophagy/autophagy and detoxifying pathways, natural compound SFN may trigger a self-defense cellular mechanism that can effectively mitigate oxidative stress commonly associated with many metabolic and age-related diseases.

氧化应激是多种病理状态的核心致病基础，涵盖癌症、神经退行性疾病与衰老进程。富含抗氧化剂的食物可维持细胞氧化还原稳态并缓解氧化应激，但其背后的分子机制尚未完全阐明。例如，萝卜硫素（sulforaphane, SFN）是一种亲电性化合物，在西兰花等十字花科蔬菜中含量丰富，可强效诱导细胞抗氧化应答。核因子红细胞2相关因子2（nuclear factor, erythroid 2 like 2, NFE2L2/NRF2）是一类转录因子，可通过抗氧化反应元件（antioxidant response elements, AREs）调控多种解毒酶的表达，被认为是SFN的潜在作用靶点。而NFE2L2/NRF2是转录因子EB（transcription factor EB, TFEB）的靶基因，TFEB作为自噬与溶酶体功能的核心调控因子，本研究证实其可被SFN强效激活。SFN通过适度活性氧（reactive oxygen species, ROS）的积累，以钙离子依赖但雷帕霉素靶蛋白激酶（mechanistic target of rapamycin kinase, MTOR）非依赖的途径诱导TFEB发生核转位。活化后的TFEB可促进自噬体与溶酶体生成相关基因的表达，而该过程已知可加速受损线粒体的清除。值得注意的是，TFEB的活性是SFN抵御急性氧化剂爆发与慢性氧化应激的必要条件。因此，天然化合物SFN可同时激活巨自噬/自噬通路与解毒通路，从而触发一种细胞自我防御机制，能够有效缓解诸多代谢疾病与年龄相关疾病中普遍存在的氧化应激。