L-F001, a Multifunctional Fasudil-Lipoic Acid Dimer Prevents RSL3-Induced Ferroptosis via Maintaining Iron Homeostasis and Inhibiting JNK in HT22 Cells
Ferroptosis, an iron-dependent form of non-apoptotic cell death, plays important roles in cerebral ischemia. Previously we have found that L-F001, a novel fasudil-lipoic acid dimer with good pharmacokinetic characters has good neuroprotection against toxin-induced cell death in vitro and in vivo. He...
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| Format: | Article |
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Frontiers Media S.A.
2022-03-01
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| Series: | Frontiers in Cellular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fncel.2022.774297/full |
| _version_ | 1811272707955752960 |
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| author | Weijia Peng Ying Ouyang Shuyi Wang Jiawei Hou Zeyu Zhu Yang Yang Ruiyu Zhou Rongbiao Pi |
| author_facet | Weijia Peng Ying Ouyang Shuyi Wang Jiawei Hou Zeyu Zhu Yang Yang Ruiyu Zhou Rongbiao Pi |
| author_sort | Weijia Peng |
| collection | DOAJ |
| description | Ferroptosis, an iron-dependent form of non-apoptotic cell death, plays important roles in cerebral ischemia. Previously we have found that L-F001, a novel fasudil-lipoic acid dimer with good pharmacokinetic characters has good neuroprotection against toxin-induced cell death in vitro and in vivo. Here, we investigated the protective effects of L-F001 against a Glutathione peroxidase 4 (GPX4) inhibitor Ras-selective lethality 3 (RSL3) -induced ferroptosis in HT22 cells. We performed MTT, Transmission Electron Microscope (TEM), Western blot, and immunofluorescence analyses to determine the protective effects of L-F001 treatment. RSL3 treatment significantly reduced HT22 cell viability and L-F001 significantly protected RSL3-induced cell death in a concentration-dependent manner and significantly attenuated Mitochondrial shrinkage observed by TEM. Meanwhile, L-F001 significantly decreased RSL3-induced ROS and lipid peroxidation levels in HT22 cells. Moreover L-F001could restore GPX4 and glutamate-cysteine ligase modifier subunit (GCLM) levels, and significantly deceased Cyclooxygenase (COX-2) levels to rescue the lipid peroxidation imbalance. In addition, FerroOrange fluorescent probe and Western blot analysis revealed that L-F001 treatment decreased the total number of intracellular Fe2+ and restore Ferritin heavy chain 1 (FTH1) level in RSL3-induced HT22 cells. Finally, L-F001 could reduce RSL3-induced c-Jun N-terminal kinase (JNK) activation, which might be a potential drug target for LF-001. Considering that L-F001 has a good anti-ferroptosis effect, our results showed that L-F001 might be a multi-target agent for the therapy of ferroptosis-related diseases, such as cerebral ischemia. |
| first_indexed | 2024-04-12T22:45:09Z |
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| issn | 1662-5102 |
| language | English |
| last_indexed | 2024-04-12T22:45:09Z |
| publishDate | 2022-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular Neuroscience |
| spelling | doaj.art-c44fcfb152e34b0e8b2b5186d1fc2c4c2022-12-22T03:13:35ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022022-03-011610.3389/fncel.2022.774297774297L-F001, a Multifunctional Fasudil-Lipoic Acid Dimer Prevents RSL3-Induced Ferroptosis via Maintaining Iron Homeostasis and Inhibiting JNK in HT22 CellsWeijia Peng0Ying Ouyang1Shuyi Wang2Jiawei Hou3Zeyu Zhu4Yang Yang5Ruiyu Zhou6Rongbiao Pi7School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, ChinaSun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, ChinaSchool of Medicine, Sun Yat-sen University, Guangzhou, ChinaSchool of Medicine, Sun Yat-sen University, Guangzhou, ChinaSchool of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, ChinaSchool of Medicine, Sun Yat-sen University, Guangzhou, ChinaSun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, ChinaSchool of Medicine, Sun Yat-sen University, Guangzhou, ChinaFerroptosis, an iron-dependent form of non-apoptotic cell death, plays important roles in cerebral ischemia. Previously we have found that L-F001, a novel fasudil-lipoic acid dimer with good pharmacokinetic characters has good neuroprotection against toxin-induced cell death in vitro and in vivo. Here, we investigated the protective effects of L-F001 against a Glutathione peroxidase 4 (GPX4) inhibitor Ras-selective lethality 3 (RSL3) -induced ferroptosis in HT22 cells. We performed MTT, Transmission Electron Microscope (TEM), Western blot, and immunofluorescence analyses to determine the protective effects of L-F001 treatment. RSL3 treatment significantly reduced HT22 cell viability and L-F001 significantly protected RSL3-induced cell death in a concentration-dependent manner and significantly attenuated Mitochondrial shrinkage observed by TEM. Meanwhile, L-F001 significantly decreased RSL3-induced ROS and lipid peroxidation levels in HT22 cells. Moreover L-F001could restore GPX4 and glutamate-cysteine ligase modifier subunit (GCLM) levels, and significantly deceased Cyclooxygenase (COX-2) levels to rescue the lipid peroxidation imbalance. In addition, FerroOrange fluorescent probe and Western blot analysis revealed that L-F001 treatment decreased the total number of intracellular Fe2+ and restore Ferritin heavy chain 1 (FTH1) level in RSL3-induced HT22 cells. Finally, L-F001 could reduce RSL3-induced c-Jun N-terminal kinase (JNK) activation, which might be a potential drug target for LF-001. Considering that L-F001 has a good anti-ferroptosis effect, our results showed that L-F001 might be a multi-target agent for the therapy of ferroptosis-related diseases, such as cerebral ischemia.https://www.frontiersin.org/articles/10.3389/fncel.2022.774297/fullL-F001ferroptosisiron homeostasislipid peroxidationc-Jun N-terminal kinase |
| spellingShingle | Weijia Peng Ying Ouyang Shuyi Wang Jiawei Hou Zeyu Zhu Yang Yang Ruiyu Zhou Rongbiao Pi L-F001, a Multifunctional Fasudil-Lipoic Acid Dimer Prevents RSL3-Induced Ferroptosis via Maintaining Iron Homeostasis and Inhibiting JNK in HT22 Cells Frontiers in Cellular Neuroscience L-F001 ferroptosis iron homeostasis lipid peroxidation c-Jun N-terminal kinase |
| title | L-F001, a Multifunctional Fasudil-Lipoic Acid Dimer Prevents RSL3-Induced Ferroptosis via Maintaining Iron Homeostasis and Inhibiting JNK in HT22 Cells |
| title_full | L-F001, a Multifunctional Fasudil-Lipoic Acid Dimer Prevents RSL3-Induced Ferroptosis via Maintaining Iron Homeostasis and Inhibiting JNK in HT22 Cells |
| title_fullStr | L-F001, a Multifunctional Fasudil-Lipoic Acid Dimer Prevents RSL3-Induced Ferroptosis via Maintaining Iron Homeostasis and Inhibiting JNK in HT22 Cells |
| title_full_unstemmed | L-F001, a Multifunctional Fasudil-Lipoic Acid Dimer Prevents RSL3-Induced Ferroptosis via Maintaining Iron Homeostasis and Inhibiting JNK in HT22 Cells |
| title_short | L-F001, a Multifunctional Fasudil-Lipoic Acid Dimer Prevents RSL3-Induced Ferroptosis via Maintaining Iron Homeostasis and Inhibiting JNK in HT22 Cells |
| title_sort | l f001 a multifunctional fasudil lipoic acid dimer prevents rsl3 induced ferroptosis via maintaining iron homeostasis and inhibiting jnk in ht22 cells |
| topic | L-F001 ferroptosis iron homeostasis lipid peroxidation c-Jun N-terminal kinase |
| url | https://www.frontiersin.org/articles/10.3389/fncel.2022.774297/full |
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