New insights: a natural small molecule isowalsuranolide targeting TrxR1/2 and triggering self-eating (autophagy) to combat cancer

Lysosomes are dynamic organelles in eukaryotic cells that play crucial roles in regulating and maintaining cellular homeostasis by degrading intracellular substances and transducing various cell signals. TFEB and TFE3 are two key transcription factors that regulate lysosomal biogenesis. TFEB/TFE3 links autophagy and lysosomal biogenesis through the transcriptional activation of genes involved in autophagosome biogenesis and autophagy-lysosomal fusion.

“Natural products are an important source of small-molecule probes in chemical biology. They are also crucial tools for exploring life phenomena, regulating biological functions, and studying biological processes such as signaling pathways,” said Xiaojiang Hao at the Kunming Institute of Botany, Chinese Academy of Sciences, and the corresponding author of the report. Therefore, their team established multiple bioactivity screening systems to evaluate the biological activities of natural products, including lysosomal biogenesis, programmed cell death, and anti-virus activity.

Tetranortriterpenoids are distributed mainly in Meliaceae family, and have been reported to have many biological activities, including anti-tumor effects. In this study, isowalsuranolide (Hdy-7), an active natural small molecule isolated from Walsura yunnanensis, was used to explore the regulatory mechanism between lysosomal biogenesis and autophagy-dependent cell death in tumor cells. Hdy-7 activated autophagy-dependent cell death by directly targeting thioredoxin reductase (TrxR1/2), and led to the rapid accumulation of a large amount of ROS in the cell by inhibiting TrxR, thus causing oxidative stress. ROS activated the p53 signaling pathway and promoted the nuclear translocation of TFEB/TFE3, which are the key lysosomal transcription factors that mediate lysosomal biogenesis. Treatment with the ROS scavenger NAC or knockdown of p53 or SESN2 attenuated the nuclear translocation of TFEB/TFE3, lysosomal biogenesis, and autophagic flux, suggesting that the TrxR1/2-p53-TFEB/TFE3 axis plays a role in maintaining lysosomal homeostasis under stress conditions other than starvation. Hdy-7 showed comparable cytotoxicity against five cancer cell lines, including Taxol resistant A549 Taxol cells. This study revealed that Hdy-7 induces ROS-mediated lysosomal biogenesis and retards cell growth by targeting TrxR1/2. This study highlights the lysosome as a regulatory hub for cellular homeostasis and as an attractive therapeutic target for a variety of lysosome-related diseases, including cancer.

The work entitled “Isowalsuranolide targets TrxR1/2 and triggers lysosomal biogenesis and autophagy via the p53-TFEB/TFE3 axis” was published in SCIENCE CHINA Life Sciences.

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