Donna Zhang, Ph.D., has dedicated her career to unraveling how cells’ defense system against oxidative stress, controlled by a gene called NRF2, can be strategically activated to prevent disease — or disarmed to help destroy cancer cells.
The Big Picture
What if the system that shields us from environmental toxins could also be harnessed to protect us from cancer? That’s the possibility that biologist Donna Zhang, Ph.D., investigates at The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology.
Zhang, the institute’s Herbert A. Wertheim Professor, has produced groundbreaking discoveries about cells’ stress response, changing how scientists understand human health and cancer biology.
Defender’s Dark Side
In healthy cells, a protein called NRF2, acts like a molecular firewall, detoxifying harmful substances like environmental pollutants and carcinogens before they can do too much damage, and protecting against diseases such as cancer, diabetes and neurodegeneration. But in some cancers, this system is paradoxically hijacked to allow tumor cells to thrive, resist treatment and evade the immune system. NRF2 is short for “nuclear factor-erythroid factor 2-related factor 2.”
Zhang says that NRF2 is vital to health, but her research has shown that in cancer, it can have a dark side.She has demonstrated that it may be possible to both strategically activate NRF2 for disease prevention, and inhibit it to treat cancer, to benefit human health. Zhang is now leading efforts to develop potential medicines designed to precisely modulate NRF2 activity. Her work is pushing her field toward translating basic research into real-world therapies for cancer and other diseases.
Detox Director
Every day, our bodies face oxidative and environmental stress from many insults. These include air pollution, industrial chemicals, and even normal metabolic byproducts of metabolism. NRF2 is the body’s built-in master regulator that turns on hundreds of protective genes, enabling cells to detoxify threats, maintain balance of reactive oxygen species, and restore cellular homeostasis.
But in cancer, this safety mechanism can be rewired. Tumor cells can overexpress NRF2, co-opting its protective signals to evade cell death, resist chemotherapy and radiation, and continue growing under harsh conditions, ultimately enabling it to spread to other tissues through a process known as metastasis.
Zhang’s research focuses on strategically activating NRF2 in healthy cells to boost their natural defenses, while selectively shutting it down in cancer cells where its overexpression fuels tumor growth and survival. Her discoveries are now driving the development of next-generation therapies to precisely target NRF2’s dual roles, safeguarding healthy tissue and eliminating cancer cells.
A Challenging Target
The NRF2 protein was once labeled “undruggable” by other scientists. It was a molecular target too slippery and difficult to target with a therapeutic intervention. Zhang and her team changed that using innovative approaches, including structure-guided design, and novel screening strategies, to successfully target NRF2. She has developed first-in-class small molecules and nanobodies that selectively modulate the NRF2 pathway. Her lab is now advancing these agents toward clinical development. She is advancing NRF2 inhibitors for lung, ovarian, and kidney cancers, and NRF2 activators for arsenic-induced metabolic diseases affecting hundreds of millions of people worldwide living in high -arsenic regions.
With tools spanning medicinal chemistry, cell biology, and mouse models of human disease, Zhang’s program stretches from lab to clinic, positioning her team to deliver precision medicines that are reshaping how we prevent or treat cancer and other human diseases.
At its core, Zhang’s work harnesses NRF2’s protective power to prevent disease — while also redefining how we treat the most therapy-resistant cancers. Her research is enabling new solutions to:
- Activate NRF2 in healthy cells to prevent damage from environmental carcinogens
- Reverse resistance to chemotherapy and radiotherapy
- Prevent metastasis by targeting NRF2-driven survival pathways
- Design smarter, safer therapies for cancer and other NRF2-related conditions
By modulating the duality of NRF2, Zhang is helping to outsmart cancer from within: preventing normal cells from turning cancerous, while eliminating cancer cells that have hijacked this pathway. Her work brings new hope to cancer patients who have exhausted conventional treatment options.
Impactful Science
Zhang’s influence extends far beyond the lab. She collaborates with clinicians, medicinal
chemists and global experts in cancer biology and toxicology to ensure her discoveries translate into real-world solutions. Her work has significantly advanced public understanding of arsenic-induced cancers and diabetes, as well as strategies for cancer prevention and treatment.
Meanwhile, she is also committed to mentoring future scientists whose work will carry forward the mission of improving human health through discovery and innovation.
She has published more than 200 peer-reviewed scientific papers, cited more than 55,000 times, making her one of the most influential figures in the NRF2 research field.
On the Horizon
Zhang’s next frontier involves pairing NRF2 inhibitors with immune-based and radiation therapies, pushing the boundaries of combinatorial cancer treatment. She is also pioneering diagnostic tools that detect NRF2-driven tumors, aiming to match the right therapy to the right patient, with precision.
Her lab is advancing companion diagnostics and exploring non-covalent activators of NRF2 for use in environmental disease prevention, offering hope to communities affected by toxic exposure.
By decoding the language of cellular defense, Zhang is reshaping how we treat not only cancer, but a broad spectrum of environmentally driven diseases, turning a once-elusive target into a powerful therapeutic opportunity.
Learn More: Understanding the Complex Role of Inflammation in Health and Disease
Make a Gift
Your donation can launch a career in science, inspire an invention or even help create a cure. Details here.