Discovery of a New Mechanism That Protects Cancer Cells from Oxidative Stress

August 4, 2026

A Promising Therapeutic Target for Disrupting Cancer Cell Defense and Promoting Cell Death

A research team formed by scientists from the University of the Ryukyus, Kindai University, and Juntendo University during their time at Yokohama City University, together with researchers from the RIKEN CSRS, has identified two enzymes involved in a previously unknown mechanism for eliminating reactive oxygen species (ROS) within cells.

The researchers found that SMG1 and DNA-dependent protein kinase (DNA-PK), protein kinases known to respond to cellular stress, directly phosphorylate NRF2, a transcription factor that plays a central role in protecting cells against oxidative stress. Activation of this SMG1/DNA-PK–NRF2 pathway enhances the elimination of intracellular reactive oxygen species.

Furthermore, the team demonstrated that inhibiting either SMG1 or DNA-PK causes excessive accumulation of intracellular reactive oxygen species in cancer cells, selectively reducing their viability primarily by inducing ferroptosis, a form of iron-dependent cell death.

These findings reveal a previously unknown mechanism by which cells protect themselves against oxidative stress and highlight SMG1 and DNA-PK as promising therapeutic targets for the development of new cancer treatments.

 

Original article

Signal Transduction and Targeted Therapy　DOI: 10.1038/s41392-026-02892-1

Y. Fujikawa, H. Imai, T. Onuki, K. Hoshino, M. A. D. Velasco, K. Matsuo, H. Kurosawa, K. Aoyagi, H. Hirose, Y. Nakamura, A. Uchiyama, K. Suzuki, M. Mizuguchi, H. Takahashi, H. Osada, N. Kagaya, K. Shin-ya, H. Satofuka, Y. Kato, H. Kuroyanagi, D. Utsumi, K. Takahashi, T. Nakayama, H. Uemura, H. Uemura, M. Yoshida, S. Ohno, A. Yamashita,

"Two stress-responsive kinases suppress ferroptosis by activating antioxidant programs under mild oxidative stress".

Contact

Minoru Yoshida; Unit Leader
Drug Discovery Seeds Development Unit
Hiroyuki Osada; Senior Visiting Scientist
Chemical Resource Development Research Unit