Liproxstatin-1 is a potent inhibitor of ferroptosis and can protect against ferroptosis-inducing agents, such as buthionine sulfoxamine (BSO), erastin, and (1S,3R)-RSL3 (RSL3). Moreover, Liproxstatin-1 does not interfere with other classical types of cell death, such as TNFα-induced apoptosis and H2O2-induced necrosis. Recently, Liproxstatin-1 has attracted the attentions as it exhibits various kinds of pharmacological activities. For example, Liproxstatin-1 can protect mouse myocardium against ischemia/reperfusion injury; Liproxstatin-1 could alleviate iron overload and attenuates morphine tolerance; Liproxstatin-1 could prevent both RSL3-induced death of primary human renal proximal TECs and GPX4 deletion-induced acute renal failure. Therefore, Liproxstatin-1 inhibits ferroptosis and promotes cell survival.[1].
The in vitro experiment demonstrated that Liproxstatin-1 could suppress ferroptosis, with an EC50 of 115.3 nM. The percentage of PI-positive cells was lower in the Liproxstatin-1 group further proving the anti-ferroptotic effect of Liproxstatin-1 (P < 0.0001). Furthermore, Liproxstatin-1 suppressed mitochondrial lipid peroxidation and increased the levels of GSH compared with the RSL-3 group (P < 0.0001). GPX4 was restored to normal levels by Liproxstatin-1 treatment.[2].
The in vivo experiment indicated that ferroptosis occurred in TECs during UUO-induced renal fibrosis and that Liproxstatin-1 was able to inhibit the ferroptosis. In addition, Liproxstatin-1 was able to prevent the morphological changes and renal function impairment that were induced by UUO in vivo.[1].
参考文献:
[1] Zhang B, et al. Liproxstatin-1 attenuates unilateral ureteral obstruction-induced renal fibrosis by inhibiting renal tubular epithelial cells ferroptosis. Cell Death Dis. 2021 Sep 11;12(9):843.
[2] Fan BY, et al. Liproxstatin-1 is an effective inhibitor of oligodendrocyte ferroptosis induced by inhibition of glutathione peroxidase 4. Neural Regen Res. 2021 Mar;16(3):561-566.
Liproxstatin-1 是一种有效的铁死亡抑制剂，可以防止铁死亡诱导剂，例如丁硫氨酸亚砜胺 (BSO)、erastin 和 (1S,3R)-RSL3 (RSL3)。此外，Liproxstatin-1 不干扰其他经典类型的细胞死亡，例如 TNFα 诱导的细胞凋亡和 H2O2 诱导的细胞坏死。最近，Liproxstatin-1 因其表现出多种药理活性而备受关注。例如，Liproxstatin-1 可以保护小鼠心肌免受缺血/再灌注损伤； Liproxstatin-1可减轻铁过载并减弱吗啡耐受性； Liproxstatin-1 可以预防 RSL3 诱导的原发性人肾近端 TEC 死亡和 GPX4 缺失诱导的急性肾功能衰竭。因此，Liproxstatin-1抑制铁死亡，促进细胞存活。[1]。
体外实验表明，Liproxstatin-1 可以抑制铁死亡，EC50 为 115.3 nM。 Liproxstatin-1 组中 PI 阳性细胞的百分比较低，进一步证明了 Liproxstatin-1 的抗铁死亡作用 (P < 0.0001)。此外，与 RSL-3 组相比，Liproxstatin-1 抑制线粒体脂质过氧化并增加 GSH 水平 (P < 0.0001)。 GPX4通过Liproxstatin-1治疗恢复到正常水平。[2]。
体内实验表明，在 UUO 诱导的肾纤维化过程中，TEC 发生了铁死亡，而 Liproxstatin-1 能够抑制铁死亡。此外，Liproxstatin-1能够阻止UUO在体内引起的形态学改变和肾功能损害。[1]。
| Cell experiment [1]: | |
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Cell lines |
ONL-93 oligodendrocytes |
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Preparation Method |
Cells were cultured and expanded in DMEM/nutrient mixture F-12, supplemented with 10% FBS and 1% penicillin-streptomycin at 37°C and 5% CO2. The culture medium was changed every 2 days. The oligodendrocyte (OLN-93 cell line) model of ferroptosis was established using RSL-3 (7.89 μM). |
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Reaction Conditions |
The cell viability after the treatment with 0, 0.5, 1.5, 2.0, 2.5, 3.0 nM Liproxstatin-1 and the treatment with 0, 0.5, 1.0, 1.5, 2.0 μM were used for the determination of EC50. |
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Applications |
Liproxstatin-1 could suppress ferroptosis, with an EC50 of 115.3 nM. Liproxstatin-1 displayed the lowest EC50 among these compounds. |
| Animal experiment [2]: | |
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Animal models |
Specific-pathogen-free 8-week-old male C57BL/6 mice |
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Preparation Method |
To establish the animal model, first, the left ureter of mice was exposed and ligated with 4-0 silk sutures, and the ligatures were dissected to prevent retrograde urinary tract infections. The sham operation was executed in a similar manner, but without ureter ligation. Twenty-four C57BL/6 mice were randomly divided into four groups: (1) sham group, (2) Liproxstatin-1 group, (3) UUO group, and (4) UUO?+?Liproxstatin-1 group. The mice in the Liproxstatin-1 and UUO?+?Liproxstatin-1 groups were intraperitoneally injected with Liproxstatin-1 for 14 consecutive days after surgery. The mice in the sham and UUO groups were intraperitoneally injected with equal volumes of 0.9% NaCl solution. |
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Dosage form |
200?μL Liproxstatin-1 (10?mg/kg/d, dissolved in DMSO and then diluted with 0.9% NaCl) |
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Applications |
Liproxstatin-1 could reduce the levels of renal iron in the UUO mice. In addition, Liproxstatin-1 treatment could significantly reduce the number of iron-positive cells in the UUO?+?Liproxstatin-1 group compared with the UUO group. Liproxstatin-1 treatment significantly decreased the GSSG/ GSH ratio in the UUO group. |
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参考文献: [1]. Fan BY, et al. Liproxstatin-1 is an effective inhibitor of oligodendrocyte ferroptosis induced by inhibition of glutathione peroxidase 4. Neural Regen Res. 2021 Mar;16(3):561-566. [2]. Zhang B, et al. Liproxstatin-1 attenuates unilateral ureteral obstruction-induced renal fibrosis by inhibiting renal tubular epithelial cells ferroptosis. Cell Death Dis. 2021 Sep 11;12(9):843. |
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