Table 3 Potential new targets and candidates for treating muscle diseases and disorder by targeting ferroptosis
Potential target/candidate | Disease or condition | Mechanisms | Ref(s) | |
|---|---|---|---|---|
Target | YY1 and YY2 | Rhabdomyosarcoma, Duchenne muscular dystrophy | YY1 and YY2 could bind to the promoter of SLC7A11 to regulate the expression level of SLC7A11. | |
| Â | Autotaxin (ENPP2) | Myocardial injury | ENPP2 regulated the expression of GPX4 and ACSL4, and enhanced MAPK and AKT signaling to protect cardiomyocytes from ferroptosis. | |
| Â | Low-density lipoprotein receptor-related protein 6 (LRP6) | Myocardial infarction | LRP6 deletion promoted ferroptosis in cardiomyocytes through regulating autophagy. | |
| Â | Ubiquitin-specific protease 7 (USP 7) | Myocardial I/R injury | Inhibition of USP7 activated p53 by inhibiting deubiquitination, and downregulated expression of TfR1, resulting in alleviating ischemia/reperfusion induced-myocardial ferroptosis. | |
| Â | Embryonic lethal abnormal vision protein 1 (ELAVL1) | Myocardial I/R injury | Knockdown or pharmacological inhibition of ELAVL1 restored GPX4 levels, suppressed ferroptosis and ameliorated myocardial ischemia/reperfusion. | |
| Â | Tripartite motif-containing protein 21 (TRIM21) | DOX-induced cardiomyopathy | TRIM21 negatively regulated the p62/Keap1/Nrf2 pathway by ubiquitinating p62, and knockdown of Trim21 upregulated the p62/Keap1/Nrf2 pathway, inhibited the mitochondrial deformation and lipid peroxidation level of cardiomyocytes, and alleviated DOX-induced cardiomyopathy | |
| Â | MITOL/MARCH5 | DOX-induced cardiomyopathy | E3 ubiquitin ligase Mitol knockdown significantly reduced mitochondrial-localized GPX4, promoted the accumulation of lipid peroxides in mitochondria and exacerbating DOX-induced ferroptosis. | |
| Â | Methyltransferase-like 14 (METTL14) | DOX-induced cardiomyopathy | METTL14 catalyzed m6A modification of the long noncoding RNA KCNQ1OT1, a miR-7-5p sponge, led to the increase of miR-7-5p target gene TfR1, promoted iron absorption and lipid peroxide production, and promoted DOX-induced ferroptosis. | |
| Â | Protein arginine methyltransferase 4 (PRMT4) | DOX-induced cardiomyopathy | PRMT4 interacted with Nrf2 to promote its enzymatic methylation, thereby inhibiting nuclear translocation of Nrf2 and subsequent GPX4 transcription and accelerating DOX-induced myocardial ferroptosis. | |
| Â | Acyl-CoA thioesterase 1 (Acot1) | DOX-induced cardiomyopathy | Acot1 overexpression inhibited DOX-induced cardiomyocyte ferroptosis. | |
| Â | Park7 | DOX-induced cardiotoxicity | Overexpression of Park7 significantly restored mitochondrial Fe-S cluster activity and iron homeostasis, inhibited ferroptosis, and salvaged DOX-induced cardiac dysfunction. | |
| Â | EP-1 | DOX-induced cardiotoxicity | EP-1 activated PKC/Nrf2 in cardiomyocytes and protected cardiomyocytes from DOX-induced ferroptosis by promoting Nrf2-driven antioxidant gene expression. | |
| Â | CREG1 | DOX-induced cardiotoxicity | CREG1 inhibits PDK4 expression by regulating FBXW7/FOXO1 pathway, thereby alleviating DOX- induced myocardial injury through inhibiting cardiac ferroptosis. | |
| Â | Heat shock factor 1 (HSF1) | Diabetic cardiomyopathy | HSF1 overexpression in cardiomyocytes improved iron homeostasis by regulating the expression of iron metabolism-related genes (such as FTH1, TfR1, and FPN), inhibited endoplasmic reticulum stress, and up-regulated the expression of GPX4, thereby inhibiting lipid peroxidation and alleviating high fat-induced ferroptosis. | |
|  | hTBK1-c.978T>A mutation | Amyotrophic lateral sclerosis | hTBK1-c.978 T > A mutation significantly increased Keap1 expression, inhibited Nrf2 signaling, and significantly inhibited neurons activity by inducing ferroptosis. | |
| Â | Frataxin | Myocardial I/R injury | Cardio-specific overexpression of frataxin improves myocardial I/R injury by regulating iron homeostasis and inhibiting ferroptosis. | |
| Â | circRNA (FEACR) | Myocardial I/R injury | FEACR regulated cardiomyocyte ferroptosis through NAMPT-SIRT1-FOXO1-FTH1 signal axis to improve myocardial infarction. | |
Candidate | Dexmedetomidine (Dex) | Sepsis | Dex reduced ferroptosis by enhancing GPX4 and reducing TfR1 and iron concentrations and attenuated sepsis-induced cardiomyocyte damage. | |
|  | β-Caryophyllene | DOX-induced cardiotoxicity | β-Caryophyllene can terminate free radical chain reactions by interacting with molecular oxygen, protecting cardiomyocytes from cellular ferroptosis. | |
| Â | Polydopamine nanoparticles (PDA NPs) | Myocardial I/R-injury | PDA NPs inhibited Fe2+ accumulation and restored mitochondrial function, and effectively reduced lipid peroxidation in myocardial tissue. | |
| Â | Etomidate | Myocardial I/R injury | Etomidate inhibited ischemia/reperfusion induced cardiac ferroptosis via activating Nrf2 pathway, increasing GSH activity and GPX4 expression, and reducing malondialdehyde and ACSL4 levels. | |
| Â | Icariin | Myocardial I/R injury | Icariin attenuated I/R-induced cardiomyocyte ferroptosis by activating the Nrf2 signaling pathway. | |
| Â | Naringenin | Myocardial I/R injury | Naringenin attenuated I/R-induced cardiomyocyte ferroptosis by activating the Nrf2 signaling pathway. | |
| Â | Astragaloside IV | Myocardial I/R injury | Astragaloside IV attenuated I/R-induced cardiomyocyte ferroptosis by activating the Nrf2 signaling pathway. | |
| Â | Cyanidin-3-glucoside (C3G) | Myocardial I/R injury | C3G attenuated the expression of oxidative stress and ferroptosis-related proteins such as TfR1, inhibited the expression of ferritinophagy-related proteins, thereby reduced the infarction area of myocardial I/R mice. | |
| Â | Isoliquiritigenin | Myocardial I/R injury | Isoliquiritigenin reduces oxidative stress by activating the Nrf2/HO-1/SLC7A11/GPX4 pathway and alleviates ferroptosis. | |
|  | Salidroside | Myocardial I/R injury | Salidroside improves myocardial I/R injury by activating of AMPKα2 and inhibiting ferroptosis. | |
| Â | CsA@ApoFn | Myocardial I/R injury | CsA in CsA@ApoFn inhibited the apoptosis of ischemic cardiomyocytes, while ApoFn inhibited the ferroptosis of ischemic cardiomyocytes by promoting the expression of GPX4 protein and decreasing the content of lipid peroxide. | |
| Â | Sulforaphane | Diabetic cardiomyopathy | Sulforaphane activated Nrf2 through AMPK signaling, upregulated ferritin and SLC7A11 levels, and inhibited cardiac ferroptosis. | |
|  | DR-Ab | DOX-induced cardiotoxicity | DR-Ab reduced ferroptosis by promoting the combination of NKA-α1 /SLC7A11 complex and alleviated DOX-induced cardiac dysfunction. | |
|  | Paeonol | DOX-induced cardiomyopathy | Paeonol promoted MFN2-mediated mitochondrial fusion by activating the PKCε-STAT3 pathway, thereby preventing DOX-induced cardiotoxicity | |
| Â | Baicalin | DOX-induced cardiomyopathy | Baicalin-peptide supramolecular self-assembled nanofibers can produce effective cardiac accumulation, which makes baicalin more effective in inhibiting ferroptosis in myocardium. | |
| Â | Protosappanin A | Myocardial I/R- and DOX-induced cardiomyopathy | Protosappanin A has protective effects on myocardial injury by targeting ACSL4/FTH1 Axis-dependent ferroptosis. | |
| Â | Metformin (Met) | Vascular calcification | Met supplementation enhanced the antioxidant capacity of vascular smooth muscle cells by activating Nrf2 signaling. | |
| Â | BRD4770 | Aortic dissection | BRD4770 attenuated lipid peroxidation and SMCs ferroptosis by inhibiting the methylation of H3K9, upregulating the mRNA levels of SLC7A11, SLC3A2, GPX4 and FSP1, promoting the activity of multiple antioxidant systems and inhibiting the production of pro-inflammatory cytokines. | |
| Â | TOP@MPDA@BY1 | Vascular restenosis | TOP@MPDA@BY1 can improve arterial stenosis by promoting ferritinophagy to induce ferroptosis in VSMCs and neointima hyperplasia. | |
| Â | Human umbilical cord blood-derived MSCs (HUCB-MSCs) exosomes | Acute myocardial infarction | HUCB-MSCs-exosomes inhibited DMT1 expression via miR-23a-3p, thereby inhibiting ferroptosis and attenuating myocardial injury. | |
| Â | Healthy cardiac muscle-derived extracellular vesicles (CEVs) | Myocardial I/R injury | ATP5a1, which is rich in CEVs, can maintain mitochondrial homeostasis and inhibit ferroptosis, thereby improving heart damage. | |
| Â | Macrophage-derived extracellular vesicles | Myocardial hypoxia injury | Macrophage-derived extracellular vesicles effectively reduce iron overload and significantly inhibit oxidative stress and ferroptosis of cardiomyocytes caused by hypoxia. | |
| Â | Gelma-exos | Aortic dissection | Gelma-exos provides sustained release of exosomes derived from mesenchymal stem cells that inhibit ferroptosis in vascular smooth muscle cells and reverse aortic degeneration. | |
