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The Zhu laboratory is interested in the function of transcription factor NRF2, a master regulator for the oxidative stress response, in physiological and pathophysiological conditions, including sickle cell disease (SCD) and liver tumors. The research focus of the lab is to understand how NRF2 mediates gene expression and how this regulatory mechanism could be exploited to achieve therapeutic goals. 

• Multi-omics study of liver tumors 

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and the third leading cause of cancer death worldwide. As the primary organ of numerous metabolic processes, the liver undergoes profound metabolic dysregulation during HCC development compared to normal hepatocytes. Key metabolic processes from glucose, fatty acid, energy generation, nucleotide, and amino acid metabolisms, are significantly altered in the disease. These alterations enhance the tumor’s ability to thrive, proliferate, and metastasize. Moreover, aberrantly produced metabolites engaged in crosstalk with other regulatory signals, influencing genomic stability, transcription regulation, and protein synthesis.

By integrating transcriptomic, epigenetic, and metabolic profiling, we identified aberrant regulation of ferroptosis, an iron-mediated programmed cell death, in both human and animal HCC models, compared to non-tumor liver tissues. This revealed a metabolic landscape enriched in anti-ferroptotic activity, suggesting systematic reprogramming of ferroptosis defense in HCC.  Currently, our lab specifically focuses on the identification of critical metabolites that present ferroptosis induction effect in liver tumor treatment. 

• NRF2 functions in Sickle Cell Disease 

Using human erythroid primary cells and an NRF2 knockout SCD mouse model, research in our lab will determine the important role of NRF2 in developmentally regulated hemoglobin switching during SCD development. Major research focus includes: 1) the role of NRF2 in the regulation of globin gene expression and switching. 2) Studies of the deleterious effect for downregulated NRF2 in SCD patient’s erythroid progenitor cells. 3) Using the NRF2 knockout SCD mouse model to determine the essential function of NRF2 on SCD pathophysiology. 4) explore small chemical compounds with NRF2 induction activity in SCD treatment. To achieve these objectives, the laboratory has successfully applied multiple molecular biotechnologies to extensively reveal the detailed molecular mechanism for NRF2 in human globin gene regulation, γ- to β-globin gene switching and their relevant for the treatment of SCD.