Dr. Donna D. Zhang
Dr. Herbert A. Wertheim Professor Center For Inflammation Science And Systems Medicine
I am honored to serve as the Wertheim UF Scripps Institute Professor at the UF Scripps Institute for Biomedical Innovation & Technology. My academic journey began with a 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, I held the position of Research Assistant Professor in the Department of Biochemistry at the University of Missouri-Columbia. In 2005, I joined the Department of Pharmacology and Toxicology at the University of Arizona, where I was promoted to full professor by 2013. During my tenure, I served as Associate Director of the Superfund Research Program from 2019 to 2022, contributing significantly to its successful renewal. In 2020, I was honored to be appointed as the inaugural Musil Family Endowed Chair in Drug Discovery. As of January 2024, I have transitioned to The UF Scripps Institute, where I will continue my research endeavors focused on NRF2 biology and toxicology.
Learn more about my research
My broad research program includes in-depth mechanistic investigations of NRF2 redox biology, arsenic pathogenesis, and the translation of basic mechanistic knowledge to preclinical drug development targeting NRF2.
My overarching vision is to harness our body’s defense systems—specifically the NRF2 response—to prevent or treat human diseases. Transcription factor NRF2 controls the cellular stress response following exposure to environmental insults. Mechanistically, NRF2 maintains cellular redox, proteostatic, metabolic, and labile iron balance through the inducible expression of target genes containing an antioxidant response element (ARE) in their promoters. Under normal conditions, NRF2 is constantly targeted for KEAP1-CUL3-mediated ubiquitylation and subsequent proteasomal degradation, thus maintaining a low basal NRF2 protein level. Upon activation, NRF2 ubiquitylation is inhibited, resulting in stabilization and nuclear translocation of NRF2, where it forms a heterodimer with sMAF and activates the transcription of ARE-containing genes. Since the discovery of the NRF2 pathway in 1999, NRF2 has been viewed as a “good” transcription factor that protects against oxidative stress-related diseases, including cancer, and controlled activation of NRF2 using NRF2-inducing compounds to prevent cancer initiation is well recognized. However, in 2008 my lab unveiled the “dark side” of NRF2—uncontrolled NRF2 activation is a driver of cancer progression, metastasis, and resistance to therapy. Furthermore, our recent findings establish a strong link between NRF2 and ovarian cancer cell resistance to ferroptosis—a novel form of cell death. Using patient-derived ovarian cancer models, we have shown that NRF2 confers resistance to IKE, a ferroptosis inducer developed to target apoptosis-resistant cancer cells. In addition, mounting amount of work from my lab has indicated that prolonged upregulation of NRF2 may also underlying molecular mechanism by which arsenic promotes cancer and diabetes. Therefore, specific NRF2 inhibitors will be powerful probes for dissecting the “dark side” role of NRF2 in disease. A big challenge in the field is that there are no NRF2-specific inhibitors available despite the efforts made towards this goal.
Chronic exposure to arsenic, an environmental contaminant that affects an estimated 160 million people worldwide, is a global public health concern correlated with an increased risk of developing certain types of cancer such as lung, bladder, and skin, as well as metabolic diseases including type II diabetes. However, despite many years of research on the adverse effects of arsenic, a critical gap still exists in our knowledge concerning the precise pathologic mechanisms of arsenic, and the generation of viable therapeutic approaches to treat arsenic-exposed populations. Over the past decade, my research has revealed that dysregulation of the NRF2 signaling pathway is a key driver of arsenic-based pathologies. Thus, the work performed in my lab is to better understand the nature of NRF2 dysregulation in arsenic-promoted cancer and type II diabetes and to generate legitimate therapeutic options to mitigate these diseases due to inevitable arsenic exposure.
The work that is performed in my lab can be summarized as followings. (i) Dissecting the NRF2 signaling network. (ii) Molecular mechanisms of NRF2 dysregulation that drive the carcinogenic and diabetogenic effects of arsenic. (iii) Development of NRF2-based therapeutics (small molecules or nanobodies) for disease prevention and intervention. (iv) the molecular biology of the cap’n’collar (CNC) family (NRF1, NRF2, and NRF3).