Cells don’t just follow a rigid script when responding to stress – they’re far more adaptable than we thought. A new study reveals that this stress response can be fine-tuned depending on the type and intensity of the threat.
This discovery, called the “split-integrated stress response,” could reshape our approach to diseases like cancer and neurodegeneration, where cells either self-destruct or dangerously adapt.
How Cells React Under Stress
When the body’s cells encounter stress, such as toxins, mutations, starvation, or other threats, they pause their normal activities. Instead, they shift focus to conserve energy, repair damage, and strengthen their defenses.
If the stress is mild or temporary, the cells recover and return to normal. But if the damage is too severe, they trigger self-destruction.
For decades, scientists believed this stress response followed a simple, linear process: sensors inside the cell detect the problem, activate a key protein, which then modifies another protein to slow or shut down normal cellular functions.
But new research from Case Western Reserve University, published today (March 26) in Nature, reveals the process is far more flexible and compartmentalized than previously thought.
The team discovered that cells can fine-tune their response depending on the type, strength, and duration of the stress. They call this more sophisticated system the “split-integrated stress response,” or s-ISR – a finding that could open the door to new ways of killing cancer cells and treating neurodegenerative diseases.
A Flexible and Adaptive System
Maria Hatzoglou, professor of the Department of Genetics and Genome Sciences at the Case Western Reserve School of Medicine and the study’s principal investigator, found for the first time a cell’s response to stress can be fine-tuned depending its nature, intensity, and duration. This flexibility provides novel insights into how cells in organisms – from yeast to humans – adapt to their environment.
“This study represents a new way of thinking about cellular stress,” Hatzoglou said. “ISR is not a one-size-fits-all system like we used to think. Instead, it can change and adjust depending on the type, strength, and length of the stress the cell is experiencing.”
Vanishing White Matter Disease: A Case Study
The study used mouse models of Vanishing White Matter Disease, which causes progressive degeneration of the brain’s white matter in children, leading to neurological problems like motor difficulties, seizures, and cognitive decline.
Hatzoglou’s research revealed that cells carrying the gene causing the disease had mutations in the key protein normally responsible for shutting down operations in the cell under stress. Somehow, the brain cells adapt and mostly function normally but are exceptionally vulnerable, self-destructing even under mild stress.
The research team, which included colleagues at Case Western Reserve, McGill University, and Karolinska Institute, determined how the cells reacted explained why patients showa significant decline in cognitive and motor abilities after relatively minor stressors like fever or mild head trauma.
Implications for Other Neurodegenerative Diseases
Other late-onset neurodegenerative diseases like multiple sclerosis and amyotrophic lateral sclerosis (better known as ALS) may share a similar mechanism, the researchers said. Diseased brain cells adapt to preserve functions under normal conditions, but modest stressors accelerate the decline.
Targeting Cancer’s Stress Adaptation
Understanding this adaptation to stress could lead to new targets for cancer chemotherapy, Hatzoglou said, because cancer cells respond to stressors like chemotherapy in one of two ways: either self-destruct or mutate to preserve their function, becoming resistant to the treatment.
With that knowledge, she said she plans to study chemotherapy-resistant breast cancer cells to better understand how those cells adapt to stress and find new targets for treating disease.
Reference: “Plasticity of the mammalian integrated stress response” by Chien-Wen Chen, David Papadopoli, Krzysztof J. Szkop, Bo-Jhih Guan, Mohammed Alzahrani, Jing Wu, Raul Jobava, Mais M. Asraf, Dawid Krokowski, Anastasios Vourekas, William C. Merrick, Anton A. Komar, Antonis E. Koromilas, Myriam Gorospe, Matthew J. Payea, Fangfang Wang, Benjamin L. L. Clayton, Paul J. Tesar, Ashleigh Schaffer, Alexander Miron, Ilya Bederman, Eckhard Jankowsky, Christine Vogel, Leoš Shivaya Valášek, Jonathan D. Dinman, Youwei Zhang, Boaz Tirosh, Ola Larsson, Ivan Topisirovic and Maria Hatzoglou, 26 March 2025, Nature.
DOI: 10.1038/s41586-025-08794-6
The study was funded by the National Institutes of Health, Case Comprehensive Cancer Center, Terry Fox Foundation Oncometabolism Team, Canadian Institutes for Health Research, Swedish Research Council, Swedish Cancer Society and National Multiple Sclerosis Society.
Never miss a breakthrough: Join the SciTechDaily newsletter.
Follow us on Google and Google News.