Dr. Zou received his Bachelor's degree from the Department of Biological Sciences and Biotechnology in Tsinghua University, Beijing, China in 2009. After a gap year working as a Research Assistant in Dr. Li Yu's group also in Tsinghua University, he joined the Gerstner Sloan Kettering Graduate School of Biomedical Sciences at Memorial Sloan Kettering Cancer Center, New York, USA to pursue his Ph.D. In graduate school, he worked with Dr. Joan Massagué on mechanisms of pluripotent stem cell differentiation and cancer metastasis. In 2016, Dr. Zou obtained his Ph.D. degree and then started his postdoctoral training in the Chemical Biology and Therapeutics Science Program at the Broad Institute of MIT and Harvard and the Department of Chemistry and Chemical Biology at Harvard University, Cambridge, Massachusetts, USA, under the mentorship of Dr. Stuart L. Schreiber. Dr. Zou’s research is published in Nature (in press), Nature Chemical Biology, Cell Stem Cell, Nature Communications, Genes&Development, and other journals. 

We are an interdisciplinary research group that is broadly interested in understanding how the chemical nature of cellular metabolites support their specific biological functions. Our current focus is to study the role of lipid metabolism in mammalian development and diseases including cancer and organ degeneration. 

The cellular lipidome contains a wide spectrum of structurally distinct lipids and collectively plays important roles in every aspect of cellular functions including membrane compartmentalization, signal transduction and energy homeostasis. Dysregulation of lipid metabolism is implicated in a large number of human diseases including obesity, neurodegeneration, cancer, and various organ failure.

While most cellular lipids contain multiple chemically reactive groups hence simultaneously belong to multiple lipid classes, there is a major gap in our understanding about what chemical properties of each lipid are contributing to a specific cellular activity and how. As a result, our knowledge about how cells organize and regulate their lipidome in response to developmental and environmental cues, and how the lipidome in turn supports cell type-specific structure and function remains scarce. Addressing these critical questions will help establish the missing link between the cellular lipidome and the genetic information flow (DNA/RNA/protein), and accelerate our therapeutic development against lipid metabolism-related diseases.

In our group, we integrate molecular, cellular, genetic, system and chemical biology approaches to discover novel lipid molecules and pathways, and identify novel therapeutic targets and drug candidates for treating human diseases associated with lipid dysregulation. Specifically, we are actively pursuing the following research directions:

1. Understanding and targeting ferroptosis in human diseases

In the past few years, the field has made rapid progress in understanding the biochemical basis of ferroptosis, developing chemical tools for reporting this cell death pathway, and identifying ferroptosis-relevant disease contexts. However, key questions remain before the power of ferroptosis-targeting strategies can be utilized to treat human diseases:

1) What is the chemical basis of lipid peroxidation and what is its physiological role in normal tissues?

2) What are the death-executing molecules or events caused by lipid peroxidation, and what types of membrane damage are necessary or sufficient to cause cell death?

3) What are the genes and pathways involved in executing lipid peroxidation? Can we target such proteins to control cellular lipid peroxidation levels?

4) What are the physiological roles of ferroptotic cell death in early development, adulthood and aging, respectively?

2. Constructing a Mammalian Lipidome Atlas to understand lineage-specific roles of the lipidome

Our prior research highlighted that cellular differentiation, tumor progression and acquisition of therapy resistance are coupled with significant changes in the cellular lipid composition, making a compelling case that the cellular lipidome exhibits a high degree of plasticity and is highly responsive to cell state transitions. Nonetheless, few cell type-specific lipid pathways have been identified despite the vast diversity of the chemical structures of cellular lipids. To accelerate the discovery of such lipids, we are developing a comprehensive “Mammalian Lipidome Atlas” (MLA) in major human and mouse cell types at representative developmental and aging stages. I envision that more novel functional lipid classes and pathways, like plasmalogens, triacylglycerides and cholesterols, will emerge from this analysis.

3. Decoding the contribution of lipid metabolism in tumorigenesis and metastasis

The development of metastatic disease accounts for >90% of cancer-associated mortality, yet few biological pathways can be exploited to inhibit metastasis. While previous studies have largely focused on the signaling and cytoskeleton changes required for metastasis such as epithelial-mesenchymal transitions (EMT), the membrane compositional changes required for supporting the enhanced motility and invasiveness of metastatic cells have not been fully examined. We are using mouse models and human patient tumor samples to investigate the molecular basis of cancer metastasis formation. We envision these studies will illuminate the membrane configurations required for supporting the enhanced motility and invasiveness of metastatic cells – an understudied aspect in metastasis research.

At the same time, we are interested in developing novel tools and technologies for detecting unique lipid species, and identifying new therapeutic modalities for targeting lipid metabolism related human diseases.

To empower efficient lipid characterizations, my lab will be actively engaged in developing novel probes and techniques for tracing, visualizing and quantifying specific lipids in vitro and in vivo. Moreover, other research areas in the lab will likely nominate novel metabolic pathways for therapeutic intervention in disease settings. Once an attractive target pathway is identified, we will integrate various chemical biology approaches, including high-throughput phenotypic screening, targeted protein degradation, and DNA-encoded small molecule screening, to develop therapeutic modalities. In addition to small molecule inhibitors, our lab is also interested in other therapeutic modalities including gene therapy and bioactive peptides. Currently, we are focusing on developing small molecule activators and inhibitors of ferroptosis for in vitro and in vivo use.

To learn more about our research, please visit: https://www.yilongzou-lab.com/research

 (# indicates corresponding author)

1. Han JR, Yang Y, Wu TW, Shi T-T, Li W, Zou Y^#. A minimally-invasive method for serial cerebrospinal fluid collection and injection in rodents with high survival rates. Biomedicines (in press)

2. Naowarojna N*, Wu TW*, Pan Z, Li M, Han JR, Zou Y^#. Dynamic Regulation of Ferroptosis by Lipid Metabolism. Antioxid Redox Signal. 2023 May 2. doi: 10.1089/ars.2023.0278. PMID: 36974367.

3. Wang F,  Naowarojna N, and Zou Y^#. Stratifying ferroptosis sensitivity in cells and tissues by photochemical activation of lipid peroxidation and imaging. STAR Protocols 2022 Mar 23;3(2):101189. doi: 10.1016/j.xpro.2022.101189. PMID: 35345595.

4. Wang F*, Graham ET*, Naowarojna N*, Shi Z*, Wang Y, Xie G, Zhou L, Salmon W, Jia J-M, Wang X, Huang Y, Schreiber SL^#, and Zou Y^#. PALP: a rapid imaging technique for stratifying ferroptosis sensitivity in normal and tumor tissues in situ. Cell Chemical Biology 2021 Nov 18:S2451-9456(21)00478-5. doi: 10.1016/j.chembiol.2021.11.001. PMID: 34813762.

Commented by: Ritho and Dixon, Cell Chemical Biology 2022

5. Pan Z*, Naowarojna N*, Wang Y, Hu M, and Zou Y^#. Neutrophil ferroptotic death promotes autoimmune pathogenesis. SCIENCE CHINA Life Sciences (Invited Commentary) 2021 Oct 27. doi: 10.1007/s11427-021-2014-4. PMID: 34716854.

6. Shi Z*, Naowarojna N*, Pan Z, Zou Y^#. Multifaceted mechanisms mediating cystine starvation-induced ferroptosis. Nature Communications 2021 Aug 09. doi: 10.1038/s41467-021-25159-5. (*co-first author)

7. Zou Y*^,#, Henry WS*, Ricq EL*, Graham ET, Maretich P, Paradkar S, Phadnis VV, Boehnke N, Deik AA, Reinhardt F, Eaton JK, Ferguson B, Wang W, Fairman J, Keys H, Dančík V, Clish CB, Clemons PA, Hammond PT, Boyer LA, Weinberg RA^#, and Schreiber SL^#. Plasticity in ether-lipids promote ferroptosis susceptibility and evasion. Nature 585(7826): 603-608. doi: 10.1038/s41586-020-2732-8. (*co-first author, ^#co-corresponding author)

Commented by:

· Conrad et al., Cell Research 2020;

· Tang and Kroemer, Signal Transduction and Targeted Therapies, 2020.

· Lee, Zhuang and Gan, Journal of Genetics and Genomics, 2021

· Balgoma and Hedeland, Trends in Endocrinology and Metabolism 2021

8. Zou Y^# & Schreiber SL^#. Progress in understanding ferroptosis and challenges in its targeting for therapeutic benefit. Cell Chemical Biology 2020 April; 27(4): 463-471. https://doi.org/10.1016/j.chembiol.2020.03.015 (Perspective) (^#co-corresponding author).

9. Zou Y*^,#, Li H*, Graham ET, Deik AA, Eaton JK, Wang W, Sandoval-Gomez G, Clish C, Doench JG, & Schreiber SL^#. Cytochrome P450 oxidoreductase contributes to phospholipid peroxidation in ferroptosis. Nature Chemical Biology 2020 Mar;16(3):302-309.  PMID: 32080622. doi: https://doi.org/10.1038/s41589-020-0472-6 (*co-first author, ^#co-corresponding author)

Commented by: Gan et al., Protein & Cell 2021.

Collected in: Hadian and Stockwell, Snapshot: Ferroptosis Cell 2020

10. Aragón A*, Wang Q*, Zou Y*, Morgani SM, Ruiz L, Kaczmarska Z, Su J, Torner C, Tian L, Hu J, Shu W, Agrawal S, Márquez JA, Hadjantonakis A-K, Macias MJ, and Massagué J. Structural basis for distinct roles of SMAD2 and SMAD3 in FOXH1 pioneer directed TGF-β signaling. Genes&Development 2019 Nov 1;33(21-22):1506-1524. doi:10.1101/gad.330837.119. (*co-first author, listed in alphabetical order.)

11. Li H, Ning S, Ghandi M, Kryukov GV, Gopal S, Deik AA, Souza A, Pierce K, Keskula P, Hernandez D, Ann J, Shkoza D, Apfel V, Zou Y, Vazquez F, Barretina J, Pagliarini RA, Galli GG, Root DE, Hahn WC, Tsherniak A, Giannakis M, Schreiber SL, Clish CB, Garraway LA, and Sellers WR. The landscape of cancer cell line metabolism. Nature Medicine 2019 May;25(5):850-860. PMID: 31068703.

12. Zou Y, Palte MJ, Deik AA, Li H, Eaton JK, Wang W, Tseng Y-Y, Deasy R, Alimova M, Dančik V, Leshchiner ES, Viswanathan VS, Signoretti S, Choueiri TK, Boehm JS, Wagner BK, Doench J, Clish CB, Clemons PA, and Schreiber SL. A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis. Nature Communications 2019 Apr 8;10(1):1617. PMID: 30962421. doi: https://doi.org/10.1038/s41467-019-09277-9

13. Su J, Morgani SM, David CJ, Wang Q, Er EE, Huang Y-H, Basnet H, Zou Y, Shu W, Hendrickson RC, Soni RK, Hadjantonakis A-K, and Joan Massagué. TGF-β Orchestrates Fibrogenic and Developmental EMTs Through the RAS Effector RREB1. Nature 2020 Jan; 577(7791): 566-571. PMID: 31915377.

14. Er EE, Valiente M, Ganesh K, Zou Y, Agrawal S, Griscom B, Giancotti F, Schachner M, Malladi S, and Massagué J. Pericytic Spreading of Disseminated Cancer Cells Activates YAP for Metastatic Outgrowth. Nature Cell Biology 2017 July 23. PMID: 30038252.

15. Martin-Malpartida P, Batet M, Kaczmarska Z, Freier R, Gomes T, Aragon E, Zou Y, Wang Q, Xi Q, Ruiz L, Vea A, Marquez JA, Massagué J and Macias M. Structural basis for genome wide recognition of 5-bp GC motifs by SMAD transcription factors. Nature Communications 2017 Dec 12; 8(1):2070. PMID: 29234012.

16. Boire A, Zou Y, Shieh J, Macalinao DG, Pentsova E and Massagué J. Complement Component 3 Adapts the Cerebrospinal Fluid for Leptomeningeal Metastasis. Cell 2017 Mar 9;168(6):1101-1113. PMID: 28283064

17. Wang Q*, Zou Y*, Nowotschin S, Li Q, Soh C-L, Kim SY, Xi Q, Zhang C, Su J, Shu W, Huangfu D, Hadjantonakis A-K and Massagué J.  The p53 family coordinates Wnt and Nodal Inputs for mesendoderm differentiation of embryonic stem cells. Cell Stem Cell 2017 Jan 5;20(1):70-86. doi: https://doi.org/10.1016/j.stem.2016.10.002. PMID: 27889317. (*Co-first author)

Commented by:

· Hamilton and Brickman, Cell Stem Cell 2017

· Okuda, Uranishi and Suzuki, Stem Cell Investigation 2017

18. Malladi S, Macalinao DG, Jin X, He L, Basnet H, Zou Y, de Stanchina E and Massagué J. Metastatic latency and immune evasion through autocrine inhibition of WNT. Cell 2016 Mar 24;165(1):45-60. PMID: 27015306.

19. David CJ, Huang Y-H, Chen M, Su J, Zou Y, Bardeesy N, Iacobuzio-Donahue CA and Massagué J. TGF-β tumor suppression through a lethal EMT. Cell 2016 Feb 25;164(5):1015-30. PMID: 26898331.

20. Obenauf AC, Zou Y*, Ji AL*, Vanharanta S, Shu W, Shi H, Kong X, Bosenberg MC, Wiesner T, Rosen N, Lo RS and Massagué J. Therapy-induced tumour secretomes promote resistance and tumour progression. Nature. 2015 Apr 16;520(7547):368-72. PMID: 25807485. (*Equal contribution)

21. Vanharanta S, Marney CB, Shu W, Valiente M, Zou Y, Mele A, Darnell RB and Massagué J. Loss of the multifunctional RNA-binding protein RBM47 as a source of selectable metastatic traits in breast cancer. Elife. 2014 Jun 4;3. PMID: 24898756.

22. Ji AL, Obenauf AC, Zou Y, Vanharanta S, Jin X and Massagué J. Selection for vemurafenib resistant melanoma cells leads to an increase in metastatic potential. Pigment Cell&Melanoma Research. 2013 Nov 1;26(6): 962-963.

23. Zhang XH, Jin X, Malladi S, Zou Y, Wen YH, Brogi E, Smid M, Foekens JA and Massagué J. Selection of bone metastasis seeds by mesenchymal signals in the primary tumor stroma. Cell. 2013 Aug 29;154(5):1060-73. PMID: 23993096.

24. Morris LG, Kaufman AM, Gong Y, Ramaswami D, Walsh LA, Turcan Ş, Eng S, Kannan K, Zou Y, Peng L, Banuchi VE, Paty P, Zeng Z, Vakiani E, Solit D, Singh B, Ganly I, Liau L, Cloughesy TC, Mischel PS, Mellinghoff IK and Chan TA. Recurrent somatic mutation of FAT1 in multiple human cancers leads to aberrant Wnt activation. Nature Genetics. 2013 Mar;45(3):253-61. PMID: 23354438.

25. Chen R, Zou Y, Mao D, Sun D, Gao G, Shi J, Liu X, Zhu C, Yang M, Ye W, Hao Q, Li R and Yu L. The general amino acid control pathway regulates mTOR and autophagy during serum/glutamine starvation. Journal of Cell Biology. 2014 Jul 21;206(2):173-82. PMID: 25049270.

26. Zhao Q, Li S, Xue F, Zou Y, Chen C, Bartlam M and Rao Z. Structure of the main protease from a global infectious human coronavirus, HCoV-HKU1. Journal of Virology. 2008 Sep;82(17):8647-55. PMID: 18562531.

Email: zouyilong@westlake.edu.cn 

We have several open positions for postdocs, graduate students and research assistants. Our lab is committed to training the next generation of scientists. We endeavor to provide an innovative, rigorous, and collegial research environment for our trainees, and offer continuous support for the career growth of young scientists. 

Please visit https://www.yilongzou-lab.com/join-us-1 for more information.