(1S,3R)-RSL3

(1S,3R)-RSL3 is a ferroptosis inducer and is canonically known as an inhibitor of glutathione peroxidase 4 (GPX4).^1,2,3 It inhibits GPX4 in a context-dependent manner: (1S,3R)-RSL3 inhibits GPX4 in the presence of cell cytosol or recombinant human 14-3-3ε, an adaptor protein, but does not inhibit recombinant human selenocysteine-containing GPX4 or purified rat testis GPX4, when used at a concentration of 100 µM.^4,5 (1S,3R)-RSL3 (50 nM) inhibits peroxidase activity in GPX4-overexpressing COH-BR1 breast cancer cell lysates.¹ It also inhibits thioredoxin reductase 1 (TrxR1; IC₅₀ = 7.9 µM in a cell-free assay).⁴ (1S,3R)-RSL3 is selectively cytotoxic to H-Ras^V12-expressing BJeLR cells over wild-type Ras-expressing BJeH cells (EC₅₀s = 0.01 and 2 µM, respectively) and induces lipid peroxidation, a hallmark of ferroptosis, in Pfa1 fibroblasts when used at a concentration of 100 nM.^1,2 In vivo, (1S,3R)-RSL3 (100 mg/kg) prevents tumor formation and inhibits tumor growth in BJeLR mouse xenograft models.¹

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1. Yang, W.S., SriRamaratnam, R., Welsch, M.E., et al. Regulation of ferroptotic cancer cell death by GPX4. Cell 156(1-2), 317-331 (2014).

2. Kagan, V.E., Mao, G., Qu, F., et al. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat. Chem. Biol. 13(1), 81-90 (2017).

3. Yang, W.S., and Stockwell, B.R. Ferroptosis: Death by lipid peroxidation. Trends Cell Biol. 26(3), 165-176 (2016).

4. Cheff, D.M., Huang, C., Scholzen, K.C., et al. The ferroptosis inducing compounds RSL3 and ML162 are not direct inhibitors of GPX4 but of TXNRD1. Redox Biol. 62, 102703 (2023).

5. Vučković, A.-M., Travain, V.B., Bordin, L., et al. Inactivation of the glutathione peroxidase GPx4 by the ferroptosis-inducing molecule RSL3 requires the adaptor protein 14-3-3ε. FEBS Lett. 594(4), 611-624 (2020).

Zhang, L.J., Salekeen, R., Soto-Palma, C., et al. Article polyunsaturated lipid senolytics exploit a ferroptotic vulnerability in senescent cells. Cell Press Blue 1(1), 100004 (2026).

Nakamura, T., Hipp, C., Mourão, A.S.D., et al. Phase separation of FSP1 promotes ferroptosis. Nature 619, 371-377 (2023).

Wang, M.-E., Chen, J., Lu, Y., et al. RB1-deficient prostate tumor growth and metastasis are vulnerable to ferroptosis induction via the E2F/ACSL4 axis. J. Clin. Invest. 133(10), e166647 (2023).

Liu, X., Nie, L., Zhang, Y., et al. Actin cytoskeleton vulnerability to disulfide stress mediates disulfidptosis. Nat. Cell. Biol. 25(3), 404-414 (2023).

Yoshioka, H., Kawamura, T., Muroi, M., et al. Identification of a small molecule that enhances ferroptosis via inhibition of ferroptosis suppressor protein 1 (FSP1). ACS Chem Biol. 17(2), 483-491 (2022).

Hendricks, J.M., Doubravsky, C., Wehri, E., et al. Identification of structurally diverse FSP1 inhibitors that sensitize cancer cells to ferroptosis. Cell Chem. Biol. 30(9), P1090-P1103 (2022).

­Wang, F., Graham, E.T., Naowarojna, N., et al. PALP: A rapid imaging technique for stratifying ferroptosis sensitivity in normal and tumor tissues in situ. Cell Chem. Bio. 29, 157-170 (2022).

Li, Z., Ferguson, L., Deol, K.K., et al. Ribosome stalling during selenoprotein translation exposes a ferroptosis vulnerability. Nat. Chem. Biol. (2022).

Mishima, E., Ito, J., Wu, Z., et al. A non-canonical vitamin K cycle is a potent ferroptosis suppressor. Nature 608(7924), 778-783 (2022).

Kobayashi, S., Harada, Y., Homma, T., et al. Characterization of a rat monoclonal antibody raised against ferroptotic cells. J. Immunol. Methods 489, 112912 (2021).

Nagakannan, P., Islam, M.I., Conrad, M., et al. Cathepsin B is an excutioner of ferroptosis. Biochim. Biophys. Acta Mol. Cell Res. 1868(3), 118928 (2021).

Soriano-Castell, D., Currais, A., and Maher, P. Defining a pharmacological inhibitor fingerprint for oxytosis/ferroptosis. Free Radic. Biol. Med. S0891-5849(21), (2021).

Zheng, J., Sato, M., Mishima, E., et al. Sorafenib fails to trigger ferroptosis across a wide range of cancer cell lines. Cell Death Dis. 12(7), 698 (2021).

Kremer, D.M., Nelson, B.S., Lin, L., et al. GOT1 inhibition primes pancreatic cancer for ferroptosis through the autophagic release of labile iron. bioRxiv (2020).

Hu, S., Sechi, M., Singh, P.K., et al. A novel redox modulator induces a GPX4-mediated cell death that is dependent on iron and reactive oxygen species. J. Med. Chem. 63(17), 9838-9855 (2020).

Ding, C.-K.C., Rose, J.W., Sun, T., et al. MESH1 is a cytosolic NADPH phosphatase that regulates ferroptosis. Nat. Metab. 2(3), 270-277 (2020).

Yi, J., Zhu, J., Wu, J., et al. Oncogenic activation of PI3K-AKT-mTOR signaling suppresses ferroptosis via SREBP-mediated lipogenesis. Proc. Natl. Acad. Sci. USA 202017152 (2020).

Bersuker, K., Hendricks, J., Li, Z., et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature 575(7784), 688-692 (2019).

Wang, W., Green, M., Choi, J.E., et al. CD8⁺ T cells regulate tumour ferroptosis during cancer immunotherapy. Nature 569(7755), 270-274 (2019).