NTHU Research Uncovers Cancer Cell Vulnerability: A Dual Assault Triggers Ferroptosis
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Antioxidants have long been regarded as essential for protecting cells and maintaining health. However, a research team led by Professor Wen-Jing Wang from the Department of Life Science at National Tsing Hua University (NTHU) has recently discovered that glutathione (GSH), a common antioxidant in the human body, plays a far more complex role in cancer cells and may even be a key factor enabling their survival. This study reveals a critical metabolic pathway that influences cancer cell viability and proposes a strategy to induce cancer cell self-destruction. The findings were published in the top-tier international journal Advanced Science, offering a novel perspective for cancer therapy.
The research shows that glutathione not only helps cells resist oxidative stress but also binds to a key metabolic enzyme known as pyruvate kinase M2 (PKM2), maintaining it in its most active tetrameric form. PKM2 functions like an energy switch within the cell, directly determining whether cancer cells can rapidly acquire energy and biosynthetic materials to sustain continuous growth.
Professor Wang uses a driving analogy to explain the mechanism: when cancer cells lose the protective effect of glutathione while simultaneously being forced to keep PKM2 running at high speed, it is akin to facing both “brake failure” and “accelerator stuck” at the same time. This dual blow leads to metabolic imbalance and excessive lipid peroxidation stress, ultimately activating a self-destructive mechanism known as ferroptosis. In animal experiments, this strategy has successfully suppressed tumor growth.
The first author of the study, Tsan-Ran Chen, noted that the activity of cellular energy metabolism enzymes is regulated by highly complex mechanisms. Through a series of screening approaches and structural biology analyses, the research team identified a new regulatory mechanism and revealed the potential “double-edged” nature of antioxidants in cancer cells. If this metabolic axis can be precisely controlled in the future, it may be possible to drive cancer cells toward self-destruction under stress, leading to more effective therapeutic strategies.
Through large-scale cancer data analysis, the team also identified another key molecule, SLC7A11, which acts as a “logistics supply system” for cancer cells by regulating the production and supply of glutathione. Higher expression levels of SLC7A11 enable cancer cells to produce more glutathione and resist ferroptosis, and its expression is strongly associated with higher malignancy and poorer prognosis. Based on these findings, the researchers propose the “GSH–PKM2–SLC7A11” metabolic axis as an important future direction for precision cancer therapy research.
This study integrates diverse research approaches, including structural biology, cell-based experiments, animal tumor models, and cancer big data analysis. Notably, the team successfully resolved the three-dimensional structure of PKM2 bound to glutathione, unveiling for the first time the operational secret of a critical “structural switch” in cancer cell proteins.
The research achievements have received international recognition. The work was honored with the Rising Star Award at the 19th Asian Crystallographic Association Conference (AsCA 2025) and received the “Taiwan Glory Award” at the 31st User Meeting and Symposium of the National Synchrotron Radiation Research Center.
Tsan-Ran Chen is also the first student in Taiwan to obtain a dual doctoral degree from NTHU and Osaka University, highlighting the university’s long-term commitment and success in cultivating interdisciplinary and international research talent. “The dual-degree program provides a rare opportunity to deeply engage in daily research in different laboratories and to access diverse techniques such as structural biology and cell imaging,” Chen said, adding that this training inspired more flexible and multifaceted thinking in his research.
This work represents the result of interdisciplinary, inter-institutional, and international collaboration. The research team has long collaborated closely with Academia Sinica Academician and Taipei Medical University Chair Professor Hsing-Chien Kung, National Yang Ming Chiao Tung University Vice President Mu-Hwa Yang, Associate Professor Jun-Yu Lin, Professor Mei-Ling Cheng of Chang Gung University, as well as Professor Yasushi Hiraoka and Professor Noriko Haraguchi from Osaka University. The team also jointly participated in the National Science and Technology Council–funded “T-Star Taiwan Cancer Precision Medicine Center Program,” led by Academia Sinica Academician Ming-Chi Hung, working together to advance precision cancer therapy research.