Investigating the molecular mechanism and metabolic basis of human diseases, with the aim to improve clinical treatment of tumors, pulmonary fibrosis, ageing, and other pathological disorders

Dr. Zhu’s current research aims to explore the molecular mechanism of human diseases from the perspective of cellular metabolism. The acquisition and utilization of nutrients by various cells in the human body provide the energy and molecular basis for all physiological and pathological processes. Dr. Zhu and his research team use molecular and cellular biology techniques, metabolomics approaches and animal models to study fundamental biological questions that are related to cancer, pulmonary fibrosis and ageing. Dr. Zhu’s previous scientific achievements include:

· The role of mitochondrial NADP (H) in proline and collagen biosynthesis

Mitochondria are central organelles of metabolism in cells. It is not well-studied how mitochondrial metabolic network functions to balance biosynthetic activities with redox homeostasis. Dr. Zhu’sworkwas the first to demonstrate that in proliferating cells, mitochondrial NADP(H) is notrequiredfor antioxidant response, but is essential for de novo proline biosynthesis. Because proline is a major component of collagen proteins in the human body, the study also shows that mitochondrial NADP(H)isrequired for collagen production that is characteristic of pulmonary fibrosis. This work was published inScienceand received extensive scientific media reports. Dr. Zhu also applied for a United States patent related to these findings as a major inventor.

· Mutant p53 co-opt epigenetic pathways to promote tumor growth

Mutationsinthe p53 tumor suppressor gene are the most commonly observed genetic alterations in human cancers. Mutated forms of p53 protein not only lose the ability to suppress tumorigenesis, but instead, acquire neomorphic functions to promote tumor progression, although the molecular mechanism underlying mutant p53 “gain-of-function” was not well-understood. Dr. Zhu’s study revealed that mutant p53 can upregulate the expression of various chromatin-modifying enzymes, thereby promoting tumor cell growth. Inhibition of these enzymes can effectively decrease the growth rate of tumor cells carrying p53 mutations. This work was published in Nature, and the findings led to a United States invention patent.

· The regulation of de novo cysteine biosynthesis in cancer cells

Tumor growth requires continuous consumption of nutrients in the surrounding tumor microenvironment in order to support biomass accumulation and tumor cell division. Tumor cells have differential requirement for different nutrients. Compared to normal tissues, cysteine often appears as one of the most depleted nutrients in the tumor microenvironment. Dr. Zhu’s work demonstrated that tumor cells often upregulate their ability to synthesize cysteine endogenously in response to cysteine deficit, and that perturbations in the cysteine biosynthesis pathway can effectively inhibit tumor growth. These findings were published and highlighted inCell Metabolism.

· PI3K signaling pathway mediates ferroptosis resistance in cancer cells

Oncogenic mutations of PI3K are frequently observed in human tumors. Dr. Zhu’s work revealed that activation of signaling pathways downstream of PI3K can suppress ferroptotic cell death in tumors, thereby promoting cancer cell survival. The study also showed that combining the inhibition of PI3K signaling pathway with the induction of ferroptosis can lead to profound tumor regression in mouse models of breast cancer and prostate cancer that harbor PI3K activation. This work was published in PNAS, and resulted in a United States patent application.

· Chromatin degeneration during cellular senescence ageing

Cellular senescence is a form of irreversible cell cycle arrest, which is enriched in aged tissues and organs, and is characterized by the secretion of inflammatory factors. Dr. Zhu participated in a series of studies that delineated the epigenetic changes during cellular senescence, demonstrating that nuclear autophagy mediates the degradation of chromatin components during senescence and promotes inflammatory response by activating innate immunity pathways. These findings were published in Nature, Cell Reports and Genes & Development, and together provided the mechanistic basis for future studies of cancer and other age-related diseases.