Sulforaphene (LFS-01) is the major chemical constituent of Raphanus sativus, a medicinal herb used for over a thousand years in traditional Chinese medicine. Here we identified that LFS-01 can selectively eradicate lymphoma cells while sparing normal lymphocytes by triggering concomitant mitophagy and apoptosis. We demonstrated that LFS-01 can retain Nrf2 in the nucleus by covalently modulating CRM1 and consequently upregulate p62/SQSTM1, an essential structural component of the autophagosomes during mitophagic process. We found that LFS-01 treatment also stimulated AMPK and thereby inhibited the mTOR pathway. On the contrary, we revealed that AMPK inhibition can severely impair the LFS-01-mediated mitophagy. Transcriptomic studies confirmed that 15 autophagy-associated genes such as p62/SQSTM1, VCP and BCL2 were differentially expressed after LFS-01 treatment. Furthermore, protein interactome network analysis revealed that the events of apoptosis and the assembly of autophagy vacuole were significant upon LFS-01 exposure. Lastly, we found that LFS-01 exhibited strong efficacy in xenograft mouse model yet with the lack of apparent toxicity to animals. We concluded that LFS-01 triggered mitophagic cell death via CRM1-mediated p62 overexpression and AMPK activation. Our findings provide new insights into the mechanism of action for LFS-01 and highlight its potential applications in treating major human diseases.

萝卜丁（LFS-01）是萝卜（Raphanus sativu s ）的主要化学成分，萝卜是一种在传统中药中使用了1000多年的草药。在这里，我们确定LFS-01可以通过触发伴随的细胞吞噬作用和细胞凋亡来选择性根除淋巴瘤细胞，同时保留正常的淋巴细胞。我们证明，LFS-01可通过共价调节CRM1并因此上调p62 / SQSTM1（在自噬过程中自噬体的基本结构成分）将Nrf2保留在细胞核中。我们发现，LFS-01治疗还刺激了AMPK，从而抑制了mTOR通路。相反，我们发现AMPK抑制可严重损害LFS-01介导的线粒体。转录组学研究证实了15个自噬相关基因，例如p62 / SQSTM1LFS-01处理后，VCP和BCL2差异表达。此外，蛋白质相互作用组网络分析表明，LFS-01暴露后细胞凋亡和自噬泡组装的事件很重要。最后，我们发现LFS-01在异种移植小鼠模型中显示出强大的功效，但对动物缺乏明显的毒性。我们得出的结论是，LFS-01通过CRM1介导的p62过表达和AMPK激活来触发线粒体细胞死亡。我们的发现为LFS-01的作用机理提供了新见解，并突出了其在治疗主要人类疾病中的潜在应用。