Cellular Response to Stress Can Be Fine-Tuned

The body’s cells respond to stress—toxins, mutations, starvation or other assaults—by pausing normal functions to focus on conserving energy, repairing damaged components and boosting defenses.

If the stress is manageable, cells resume normal activity; if not, they self-destruct.

Scientists have believed for decades this response happens as a linear chain of events: sensors in the cell “sound an alarm” and modify a key protein, which then changes a second protein that slows or shuts down the cell’s normal function.

But in a new study published today in the journal Nature, researchers at Case Western Reserve University have discovered a cell’s response is more nuanced and compartmentalized—not fixed or rigid, as previously thought.

The groundbreaking research suggests this adaptive response to stress—which the researchers call “split-integrated stress response” or s-ISR—could potentially be exploited to kill cancer cells and more effectively treat neurodegenerative diseases.

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 on 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.”

The 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 explains why patients show significant decline in cognitive and motor abilities after relatively minor stressors like fever or mild head trauma.

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 decline.

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: Chen CW, Papadopoli D, Szkop KJ, et al. Plasticity of the mammalian integrated stress response. Nature. 2025. doi: 10.1038/s41586-025-08794-6

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