Overview of Our Research

Exposure to arsenic affects 160 million people worldwide, increasing the risk of developing cancer and diabetes. Donna Zhang, Ph.D. studies how arsenic induces diseases, with the goal of identifying new pharmaceuticals to prevent or treat adverse health effects resulting from arsenic exposure. NRF2 controls key aspects of the cell’s defense system by maintaining cellular redox and metabolic balance. NRF2 activation protects against acute toxicity and disease development induced by exposure to environmental toxicants, including arsenic, which is the basis of current NRF2-based drug development. However, Dr. Zhang also discovered a “dark side” of NRF2, that constant activation of NRF2 can drive cancer progression, metastasis, and resistance to therapy, as well as promote a pro-diabetic shift in metabolism, all of which occur following chronic, low-dose arsenic exposure. The goals of her project, then, are to characterize the molecular bases of diseases associated with arsenic exposure, and to identify ways in which NRF2, as well as the other NRF protein family members (NRF1 and NRF3), can be effectively harnessed to prevent or treat arsenic-induced lung cancer and Type II diabetes.

Donna D Zhang Laboratory

Meet the PI

Dr. Zhang holds the esteemed position of Wertheim UF Scripps Institute Professor at the UF Scripps Institute for Biomedical Innovation & Technology. She obtained her Ph.D. in Molecular Toxicology from the Nelson Institute of Environmental Medicine at New York University in 1997, followed by a postdoctoral fellowship at the DuPont-Haskell Laboratory. From 1999 to 2005, Dr. Zhang was a Research Assistant Professor in the Department of Biochemistry at the University of Missouri-Columbia. She joined the University of Arizona’s Department of Pharmacology and Toxicology in 2005 and was promoted to full professor by 2013. As Associate Director of the Superfund Research Program from 2019 to 2022, she played a pivotal role in the program’s successful renewal. In 2020, she became the inaugural Musil Family Endowed Chair in Drug Discovery. As of January 2024, Dr. Zhang transitioned to The UF Scripps Institute, where she continues her work in NRF2 biology and toxicology.

Dr. Zhang is a renowned toxicologist whose meticulous research has unraveled the complex interplay between the human body and environmental toxins. Her pioneering work on the cellular NRF2-KEAP1 defense system against environmental insults has positioned her as a world authority in the field. With over 180 publications in top-tier journals, Dr. Zhang’s scholarly impact is evidenced by her impressive citation count of 46,236 and an h-index of 79 (Google Scholar, as of February 6, 2024). Her research extends beyond clarifying NRF2’s regulatory mechanisms; it explores its dual roles in diseases such as cancer, diabetes, non-alcoholic fatty liver disease (NAFLD), and Parkinson’s disease. Her seminal work has led to significant advancements in novel therapeutics targeting NRF2. Her achievements have been recognized by the Society of Toxicology (SOT), as demonstrated by her receiving the SOT Achievement Award in 2012, the Distinguished Chinese American Toxicologist Award from the American Association of Chinese in Toxicology (AACT) in 2023, and the SOT Leading Edge in Basic Science Award in 2024. She is also a respected academic mentor, having guided 15 Ph.D. candidates and over 30 postdoctoral fellows towards flourishing careers in academia, industry, and editorial positions at leading journals like Cancer Cell.

Dr. Zhang’s research identified Keap1 as an E3 ubiquitin ligase, a critical regulator that targets NRF2 for ubiquitylation and subsequent degradation. Her insights into KEAP1’s cysteine residues, particularly C151, have been fundamental in understanding their role as sensors of oxidative stress and as switches that regulate the NRF2 pathway in response to environmental insults. She termed this the canonical mechanism of NRF2 activation, central to our comprehension of NRF2’s role in cellular defense. Furthermore, her team has identified and characterized several chemopreventive agents that activate NRF2, showcasing their potential in cancer prevention and the amelioration of diabetic complications.

In 2008, Dr. Zhang introduced the concept of NRF2’s dark side, showing its paradoxical role in cancer progression and chemoresistance. Her team provided substantial genetic evidence that diminishing NRF2 expression can increase the susceptibility of cancer cells to chemotherapy. Following this discovery, they identified brusatol as a potent inhibitor of the NRF2 pathway, effectively counteracting both inherent and acquired chemoresistance in cancer cells and in animal models. This discovery led other prominent cancer researchers to investigate the “oncogenic” functions of NRF2, significantly advancing the breadth of NRF2 research.

In 2010, Dr. Zhang’s group revealed that NRF2 activation could also be regulated by p62, a protein linked to autophagy, via a noncanonical pathway that does not involve KEAP1-C151. Their 2013 research resolved the conundrum of arsenic-induced carcinogenesis despite NRF2 activation; it demonstrated that arsenic prolongs NRF2 activation through this alternate pathway, which, contrary to its usual protective role, contributes to cancer development. In 2021, they were the first to demonstrate NRF2’s dark side in metabolic diseases, showing that arsenic-induced noncanonical NRF2 activation causes a pro-diabetic shift in hepatic glucose metabolism. Dr. Zhang continues to explore NRF biology passionately, aiming to develop therapeutics that modulate NRF2 activity to treat various diseases and enhance human health.

For more information on Dr. Zhang’s research and accomplishments, check out Dr. Zhangs CV