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Reply to: DHODH inhibitors sensitize to ferroptosis by FSP1 inhibition

Nature volume 619, pages E19–E23 (2023)Cite this article

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The Original Article was published on 05 July 2023

replying to E. Mishima et al. Nature https://doi.org/10.1038/s41586-023-06269-0 (2023)

Ferroptosis represents a form of cell death induced by excessive lipid peroxidation on cellular membranes1,2. Our recent study identified a defence mechanism in mitochondria mediated by dihydroorotate dehydrogenase (DHODH) via ubiquinol generation3. In the accompanying Comment4, Mishima et al. were able to reproduce our findings that DHODH deletion or treatment with the DHODH inhibitor brequinar sensitized cancer cells to ferroptosis. However, they argue that: (1) ferroptosis-sensitization phenotypes in DHODH-knockout cells are mild—therefore, DHODH has a limited role in ferroptosis regulation; (2) ferroptosis sensitization by brequinar (and other DHODH inhibitors) is mediated by their off-target effects through inhibition of ferroptosis suppressor protein 1 (FSP1), another critical mediator of ferroptosis defence5,6; and (3) our data revealing a role of mitochondrial GPX4 in regulating ferroptosis is inconsistent with the current understanding of different GPX4 isoforms. Below we provide our counter-argument and clarification.

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Fig. 1: Analyses of ferroptosis phenotypes in cells with DHODH deletion or DHODH inhibitor treatment.

Data availability

All data that support the conclusions in this manuscript are available from the corresponding author upon reasonable request.

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Acknowledgements

This research was supported by internal fund from the University of Texas MD Anderson Cancer Center.

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Authors and Affiliations

  1. Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Chao Mao, Xiaoguang Liu, Yuelong Yan & Boyi Gan

  2. The Barer Institute, Philadelphia, PA, USA

    Kellen Olszewski

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  1. Chao Mao
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Contributions

C.M. performed most of the experiments with assistance from X.L. and Y.Y. B.G., C.M. and K.O. designed the experiments. B.G. supervised the study, established collaborations, allocated funding for this study, and wrote most of the manuscript with the assistance from K.O. and C.M. All authors commented on the manuscript. We note that the author list for this Reply differs from the original paper in number and order to accurately reflect its more focused scope compared with the original work.

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Correspondence to Boyi Gan.

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Extended data figures and tables

Extended Data Fig. 1 Analyses of ferroptosis phenotypes in cells with DHODH deletion or DHODH inhibitor treatment.

a,b, DHODH, GPX4 and Vinculin protein levels in different cell lines were determined by western blotting. c–i, Chemical structures of iFSP1 (c), BQR (d), BAY-2402234 (e), AG-636 (f), DSM265 (g), PTC299 (h) and Vidofludimus (i). j–m, Cell viability measurement in HT-1080 cells treated with RSL3, AG-636 (100 μM) (j), DSM265 (100 μM) (k), PTC299 (100 μM) (l) and Vidofludimus (100 μM) (m) for 24 h. n,o, FSP1 and Vinculin protein levels in different cell lines were determined by western blotting. p, Cell viability measurement in Vector and FSP1 overexpression Hs 578T cells treated with RSL3 for 24 h. q, Cell viability measurement in HT-1080 cells treated with RSL3, BQR (1 μM) and Lip-1 (1 μM) for 24 h. r, Cell viability measurement in HT-1080 cells treated with RSL3, BAY-2402234 (1 μM) and Lip-1 (1 μM) for 24 h. In a,b,j–r, cells were grown in uridine (50 μM) supplemented medium. Data are presented as mean values +/− SD, n = 3 (j–m,p–r). Data are from three independent replicates (j–m,p–r). Western blot is representative of two independent replicates (a,b,n,o).

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Supplementary Information

This file contains the uncut gel source images for Extended Data Fig. 1.

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Mao, C., Liu, X., Yan, Y. et al. Reply to: DHODH inhibitors sensitize to ferroptosis by FSP1 inhibition. Nature 619, E19–E23 (2023). https://doi.org/10.1038/s41586-023-06270-7

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