Brent R. Stockwell

Brent R. Stockwell

Research Interest

Summary

We are using chemical and biological tools to study ferroptosis, a form of regulated cell death discovered in the Stockwell Lab. Ferroptosis is an iron-dependent form of oxidative, non-apoptotic cell death that is tightly linked to metabolism and disease.

We are exploring how ferroptosis is triggered during normal physiological processes and in disease states, and how it can be induced and inhibited for therapeutic benefit in various cancers and neurodegenerative diseases.

We cover a significant scope of chemistry and biology in our mission to define new mechanisms of cell death, to understand ferroptosis, and subsequently to discover potent therapeutics. We start with the use of computational chemistry tools to design chemical probes and drug candidates that reveal cellular and molecular mechanisms. We then use synthetic organic chemistry to produce libraries of drugs that are used in a wide range of in vitro assays to study effects on cell viability, lipid peroxidation, and gene expression. We also use metabolomics, lipidomics, CRISPR and siRNA/shRNA screening, protein expression and biochemistry, and structure elucidation. Analytical chemistry in the forms of mass spectrometry imaging and Raman spectroscopy are additionally utilized along with cell imaging to study the localization of ferroptosis inducers and inhibitors. Finally we use animal models to test our compounds in vivo.

Through the integration of biochemistry, synthetic organic chemistry, computational chemistry, biophysics, and analytical chemistry, the Stockwell Lab aims to produce potent therapeutics by determining new mechanisms of action involved in cell death and in particular, ferroptosis.

Relevant publications:

Gaschler MM, Andia AA, Liu H, Csuka JM, Hurlocker B, Vaiana CA, Heindel DW, Zuckerman DS, Bos PH, Reznik E, Ye LF, Tyurina YY, Lin AJ, Shchepinov MS, Chan AY, Peguero-Pereira E, Fomich MA, Daniels JD, Bekish AV, Shmanai VV, Kagan VE, Mahal LK, Woerpel KA, Stockwell BR. FINO2 initiates ferroptosis through GPX4 inactivation and iron oxidation. Nat Chem Biol. 2018 Apr [pubmedpdf]

Shimada K, Reznik E, Stokes ME, Krishnamoorthy L, Bos PH, Song Y, Quartararo CE, Pagano NC, Carpizo DR, deCarvalho AC, Lo DC, Stockwell BR. Copper-Binding Small Molecule Induces Oxidative Stress and Cell-Cycle Arrest in Glioblastoma-Patient-Derived Cells.Cell Chemical Biology. 2018 Mar [pubmedpdf]

Gaschler MM, Hu F, Feng H, Linkermann A, Min W, Stockwell BR. Determination of the subcellular localization and mechanism of action of ferrostatins in suppressing ferroptosis. ACS Chem Biol. 2018 Mar [pubmedpdf]

Yozwiak CE, Hirschhorn T, Stockwell BR. Towards a microparticle-based system for pooled assays of small molecules in cellular contexts. ACS Chem Biol. 2018 Jan [pubmedpdf]

Ling Y, Stockwell BR. Transforming Lipoxygenases: PE-Specific Enzymes in Disguise. Cell 2017 Oct [pubmedpdf]

Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, Fulda S, Gascon S, Hatzios SK, Kagan VE, Noel K, Jiang X, Linkermann A, Murphy ME, Overholtze M, Oyagi A, Pagnussat GC, Park J, Ran Q, Rosenfeld CS, Salnikow K, Tang D, Torti FM, Torti SV, Toyokuni S, Woerpel KA, Zhang DD Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Cell 2017 Oct [pubmedpdf]

Yang WS, Kim KJ, Gaschler MM, Patel M, Shchepinov MS, Stockwell BR. Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. Proc Natl Acad Sci USA. 2016 Aug;113(34):E4966-75 [pubmedpdf]

Shimada K, Skouta R, Kaplan A, Yang WS, Hayano M, Dixon SJ, Brown LM, Valenzuela CA, Wolpaw AJ, Stockwell BR. Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis. Nat Chem Biol. 2016 May [pubmedpdf]

Shimada K, Hayano M, Pagano N, Stockwell BR. Cell-Line Selectivity Improves the Predictive Power of Pharmacogenomic Analyses and Helps Identify NADPH as Biomarker for Ferroptosis Sensitivity. Cell Chemical Biology. 2016 Feb [pubmedpdf]

Conrad M, Angeli JPF, Vandenabeele P, Stockwell BR. Regulated necrosis: disease relevance and therapeutic opportunities. Nat Rev Drug Discov. 2016 Jan [pubmedpdf]

Yang WS, Stockwell BR. Ferroptosis: Death by lipid peroxidation. Trends Cell Biol. 2015 Nov [pubmedpdf]

Dixon SJ, Winter GE, Musavi LS, Lee ED, Snijder B, Rebsamen M, Superti-Furga G, Stockwell BR. Human haploid cell genetics reveals roles for lipid metabolism genes in nonapoptotic cell death. ACS Chem Biol. 2015 Jul;10(7):1604-9 [pubmedpdf]

Skouta R, Dixon SJ, Wang J, Dunn DE, Orman M, Shimada K, Rosenberg P, Lo D, Weinberg J, Linkermann A, Stockwell BR. Ferrostatins inhibit oxidative lipid damage and cell death in diverse disease models. J Am Chem Soc 2014 Mar 4; 136(12):4551-6 [pubmedpdf]

Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, Cheah JH, Clemons PA, Shamji AF, Clish CB, Brown LM, Girotti AW, Cornish VW, Schreiber SL, Stockwell BR. Regulation of Ferroptotic Cancer Cell Death by GPX4. Cell 2014 Jan 16; 156(1):317-331 [pubmedpdf]

Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R,Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS, Morrison B, Stockwell BR. Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death. Cell 2012 May;149(5), 1060-1072 [pubmedpdf]