RSL3, also known as (1S,3R)-RSL3, acts as an inhibitor of glutathione peroxidase 4 (GPX4), which is a ferroptosis activator. It diminishes the GPX4 protein levels and prompts ferroptotic cell death in head and neck cancer cells. Additionally, RSL3 elevates the levels of p62 and Nrf2 and deactivates Keap1 in HN3-rslR cells[1]. RSL3, within concentration of 8 μM over 72 hours, significantly decreases the viability of HN3 cells. The IC50 values are 0.48 μM for HN3 cells and 5.8 μM for HN3-rslR cells, respectively. RSL3, in concentrations ranging from 0 to 8 μM over a period of 24 hours, diminishes GPX4 protein levels, augments the expression of p62 and Nrf2, and deactivates Keap1 in HN3-rslR cells[1].
RSL3 细胞实验
Cell Line
Concentration
Treated Time
Description
References
HT22 mouse hippocampal neuronal cells
80 nM
24 hours
To evaluate the protective effect of catechol estrogens against erastin/RSL3-induced ferroptosis. Results showed that four catechol estrogens (2-OH-E1, 2-OH-E2, 4-OH-E1, and 4-OH-E2) significantly inhibited erastin/RSL3-induced cell death and reduced the accumulation of NO, ROS, and lipid-ROS.
Sci Rep. 2024 Oct 14;14(1):23988.
Pfa1 Gpx4-KO cells
300 nM
24 hours
To assess the sensitivity of FSP1 mutants to ferroptosis
Nat Struct Mol Biol. 2023 Nov;30(11):1806-1815.
Pfa1 cells
500 nM
2 days
To identify possible mutations affecting FSP1's ferroptosis-suppressive function
Nat Struct Mol Biol. 2023 Nov;30(11):1806-1815.
synovial fibroblasts
0.125 μM
12 hours
Evaluate the effect of RSL3 on ferroptosis in synovial fibroblasts, results showed RSL3 induced cell death and lipid peroxidation
Nat Commun. 2022 Feb 3;13(1):676
C4-2
0.5 μM
9 days
To evaluate the effect of RSL3 on prostate cancer cell colony formation, results showed that RSL3 significantly inhibited colony formation of prostate cancer cells.
Cancer Res. 2021 Mar 15;81(6):1583-1594.
PC3
0.125, 0.25, 0.5 μM
72 h
To evaluate the effect of RSL3 on prostate cancer cell growth, results showed that all prostate cancer cell lines were sensitive to RSL3-induced ferroptosis.
Cancer Res. 2021 Mar 15;81(6):1583-1594.
DU145
0.125, 0.25, 0.5, 1, 2, and 4 μM
72 h
To evaluate the effect of RSL3 on prostate cancer cell growth, results showed that all prostate cancer cell lines were sensitive to RSL3-induced ferroptosis.
Cancer Res. 2021 Mar 15;81(6):1583-1594.
G-361
0.5 µM
24 h
RSL3 induced ferroptosis in G-361 cells, and overexpression of miR-137 suppressed RSL3-induced ferroptosis
Cell Death Differ. 2018 Aug;25(8):1457-1472.
A375
0.1 µM
24 h
RSL3 induced ferroptosis in A375 cells, and overexpression of miR-137 suppressed RSL3-induced ferroptosis
Cell Death Differ. 2018 Aug;25(8):1457-1472.
HT29 cells
3 µM
24 h
RSL3 induced ferroptosis by increasing ROS levels and the cellular labile iron pool, leading to cell death.
Front Pharmacol. 2018 Nov 22;9:1371.
LoVo cells
3 µM
24 h
RSL3 induced ferroptosis by increasing ROS levels and the cellular labile iron pool, leading to cell death.
Front Pharmacol. 2018 Nov 22;9:1371.
HCT116 cells
3 µM
24 h
RSL3 induced ferroptosis by increasing ROS levels and the cellular labile iron pool, leading to cell death.
Front Pharmacol. 2018 Nov 22;9:1371.
PANC1 cells
0.5 µM
6 h
RSL3 induced cell death and lipid peroxidation in PANC1 cells, and CQ inhibited RSL3-induced cell death and lipid peroxidation.
Autophagy. 2021 Nov;17(11):3361-3374.
HT1080 cells
0.5 µM
6 h
RSL3 induced cell death and lipid peroxidation in HT1080 cells, and CQ inhibited RSL3-induced cell death and lipid peroxidation.
Autophagy. 2021 Nov;17(11):3361-3374.
60 human cancer cell lines
0.5 µM
3 and 6 h
RSL3 exhibits wider and stronger activity in the upregulation of MAP1LC3B-II or downregulation of SQSTM1 in 80% (48/60) or 63% (38/60) of cell lines, respectively. Both RSL3 and erastin failed to affect SLC7A11 expression, but they led to GPX4 downregulation in 12% (7/60) and 3% (2/60) of cell lines, respectively.
Autophagy. 2021 Nov;17(11):3361-3374.
SH-SY5Y cells
20 μM
To evaluate the inhibitory effect of RSL3 and erastin-induced ferroptosis in SH-SY5Y cells, it was found that ThA increased cell viability in a dose-dependent manner at concentrations of 2-16 μM.
Theranostics. 2024 Sep 23;14(16):6161-6184.
PC-12 cells
0.5 μM
4, 8, 12, 24 h
To evaluate the inhibitory effect of RSL3-induced ferroptosis in PC-12 cells, it was found that ThA significantly increased cell survival and effectively prevented ferroptosis at all observed time points.
Theranostics. 2024 Sep 23;14(16):6161-6184.
Huh7
5 μM
RSL3 significantly suppressed the viability of Huh7 cells and induced ferroptosis.
Drug Des Devel Ther. 2021 Sep 18;15:3965-3978.
HepG2
5 μM
RSL3 significantly suppressed the viability of HepG2 cells and induced ferroptosis.
Drug Des Devel Ther. 2021 Sep 18;15:3965-3978.
human epidermal keratinocytes (HEKa)
10 μM
6 h
To assess the effect of RSL3 on cell viability, results showed that RSL3 treatment significantly reduced cell viability.
J Clin Invest. 2024 Nov 21;135(2):e183219.
EOC 20 microglial cells
500 nM
5 h
To test the sensitivity to RSL3-induced ferroptosis, M1-activated cells showed high resistance to RSL3, while M0 and M2-activated cells were susceptible.
Nat Chem Biol. 2020 Mar;16(3):278-290.
Bone marrow-derived macrophages (BMDM)
500 nM
5 h
To test the sensitivity to RSL3-induced ferroptosis, M1-activated cells showed high resistance to RSL3, while M0 and M2-activated cells were susceptible.
Nat Chem Biol. 2020 Mar;16(3):278-290.
RAW 264.7 macrophages
500 nM
5 h
To test the sensitivity to RSL3-induced ferroptosis, M1-activated cells showed high resistance to RSL3, while M0 and M2-activated cells were susceptible.
Nat Chem Biol. 2020 Mar;16(3):278-290.
HK2 cells
1 μM
24 h
RSL3 induces ferroptosis in HK2 cells, leading to increased lipid peroxidation and cell death.
Redox Biol. 2023 Dec;68:102939.
RSL3 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
NSG (NOD-SCID-IL2R γ) male mice
Prostate cancer xenograft model
Intraperitoneal injection
100 mg/kg
Twice per week, until the end of the experiment
To evaluate the effect of RSL3 on tumor growth in prostate cancer xenograft models, results showed that RSL3 significantly delayed tumor growth of DU145 and PC3 xenografts.
Cancer Res. 2021 Mar 15;81(6):1583-1594.
Nude mice
Subcutaneous tumor model
Intraperitoneal injection
15 mg/kg
Twice every other day for 20 days
Knockdown of miR-137 enhanced erastin-induced ferroptosis and inhibited tumor growth
Cell Death Differ. 2018 Aug;25(8):1457-1472.
Mice
C57BL/6 mice
Topical application
10 μM (120 μL)
Twice daily for 2 weeks
To evaluate the effect of RSL3 on mouse skin, results showed that RSL3 increased ferroptosis-specific oxPE species in the epidermis but did not induce psoriasis-like epidermal changes or immune cell infiltration.
J Clin Invest. 2024 Nov 21;135(2):e183219.
Mice
Zymosan-induced peritonitis model
Intraperitoneal injection
40 mg/kg
Single injection, lasting 5 hours
To test the effect of RSL3 on M2 macrophages in vivo, RSL3 significantly reduced the number of M2 macrophages, while the NO donor DETA NONOate suppressed this reduction.
Nat Chem Biol. 2020 Mar;16(3):278-290.
Mice
AKI-CKD model
Intraperitoneal injection
5 mg/kg
Daily for 14 days
RSL3 pretreatment significantly increased renal fibrosis and ferroptosis in AKI-CKD model mice and abrogated the anti-ferroptosis and renoprotective effects of RGFP966.
Redox Biol. 2023 Dec;68:102939.
RSL3 动物研究
Animal study
Administering RSL3 at a dosage of 100 mg/kg, intratumorally twice per week for a duration of 20 days, notably hampers tumor growth when used alongside Trigonelline in mice implanted with HN3R cells[1].
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