Ferrostatin-1 inhibits fibroblast fibrosis in keloid by inhibiting ferroptosis.
Humans
Ferroptosis
/ drug effects
Keloid
/ pathology
Fibroblasts
/ drug effects
Cyclohexylamines
/ pharmacology
Fibrosis
/ metabolism
Phenylenediamines
/ pharmacology
NF-E2-Related Factor 2
/ metabolism
Phospholipid Hydroperoxide Glutathione Peroxidase
/ metabolism
Male
Lipid Peroxidation
/ drug effects
Female
Adult
Iron
/ metabolism
Amino Acid Transport System y+
/ metabolism
Receptors, Transferrin
/ metabolism
Piperazines
/ pharmacology
Actins
/ metabolism
Mitochondria
/ drug effects
Membrane Potential, Mitochondrial
/ drug effects
Erastin
Ferroptosis
Ferrostatin-1
Fibroblasts
Fibrosis
Keloid
Journal
PeerJ
ISSN: 2167-8359
Titre abrégé: PeerJ
Pays: United States
ID NLM: 101603425
Informations de publication
Date de publication:
2024
2024
Historique:
received:
02
02
2024
accepted:
20
05
2024
medline:
18
6
2024
pubmed:
18
6
2024
entrez:
18
6
2024
Statut:
epublish
Résumé
Keloid is a chronic proliferative fibrotic disease caused by abnormal fibroblasts proliferation and excessive extracellular matrix (ECM) production. Numerous fibrotic disorders are significantly influenced by ferroptosis, and targeting ferroptosis can effectively mitigate fibrosis development. This study aimed to investigate the role and mechanism of ferroptosis in keloid development. Keloid tissues from keloid patients and normal skin tissues from healthy controls were collected. Iron content, lipid peroxidation (LPO) level, and the mRNA and protein expression of ferroptosis-related genes including solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4), transferrin receptor (TFRC), and nuclear factor erythroid 2-related factor 2 (Nrf2) were determined. Mitochondrial morphology was observed using transmission electron microscopy (TEM). Keloid fibroblasts (KFs) were isolated from keloid tissues, and treated with ferroptosis inhibitor ferrostatin-1 (fer-1) or ferroptosis activator erastin. Iron content, ferroptosis-related marker levels, LPO level, mitochondrial membrane potential, ATP content, and mitochondrial morphology in KFs were detected. Furthermore, the protein levels of α-smooth muscle actin (α-SMA), collagen I, and collagen III were measured to investigate whether ferroptosis affect fibrosis in KFs. We found that iron content and LPO level were substantially elevated in keloid tissues and KFs. SLC7A11, GPX4, and Nrf2 were downregulated and TFRC was upregulated in keloid tissues and KFs. Mitochondria in keloid tissues and KFs exhibited ferroptosis-related pathology. Fer-1 treatment reduced iron content, restrained ferroptosis and mitochondrial dysfunction in KFs, Moreover, ferrostatin-1 restrained the protein expression of α-SMA, collagen I, and collagen III in KFs. Whereas erastin treatment showed the opposite results. Ferroptosis exists in keloid. Ferrostatin-1 restrained ECM deposition and fibrosis in keloid through inhibiting ferroptosis, and erastin induced ECM deposition and fibrosis through intensifying ferroptosis.
Sections du résumé
Background
UNASSIGNED
Keloid is a chronic proliferative fibrotic disease caused by abnormal fibroblasts proliferation and excessive extracellular matrix (ECM) production. Numerous fibrotic disorders are significantly influenced by ferroptosis, and targeting ferroptosis can effectively mitigate fibrosis development. This study aimed to investigate the role and mechanism of ferroptosis in keloid development.
Methods
UNASSIGNED
Keloid tissues from keloid patients and normal skin tissues from healthy controls were collected. Iron content, lipid peroxidation (LPO) level, and the mRNA and protein expression of ferroptosis-related genes including solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4), transferrin receptor (TFRC), and nuclear factor erythroid 2-related factor 2 (Nrf2) were determined. Mitochondrial morphology was observed using transmission electron microscopy (TEM). Keloid fibroblasts (KFs) were isolated from keloid tissues, and treated with ferroptosis inhibitor ferrostatin-1 (fer-1) or ferroptosis activator erastin. Iron content, ferroptosis-related marker levels, LPO level, mitochondrial membrane potential, ATP content, and mitochondrial morphology in KFs were detected. Furthermore, the protein levels of α-smooth muscle actin (α-SMA), collagen I, and collagen III were measured to investigate whether ferroptosis affect fibrosis in KFs.
Results
UNASSIGNED
We found that iron content and LPO level were substantially elevated in keloid tissues and KFs. SLC7A11, GPX4, and Nrf2 were downregulated and TFRC was upregulated in keloid tissues and KFs. Mitochondria in keloid tissues and KFs exhibited ferroptosis-related pathology. Fer-1 treatment reduced iron content, restrained ferroptosis and mitochondrial dysfunction in KFs, Moreover, ferrostatin-1 restrained the protein expression of α-SMA, collagen I, and collagen III in KFs. Whereas erastin treatment showed the opposite results.
Conclusion
UNASSIGNED
Ferroptosis exists in keloid. Ferrostatin-1 restrained ECM deposition and fibrosis in keloid through inhibiting ferroptosis, and erastin induced ECM deposition and fibrosis through intensifying ferroptosis.
Identifiants
pubmed: 38887622
doi: 10.7717/peerj.17551
pii: 17551
pmc: PMC11182022
doi:
Substances chimiques
Cyclohexylamines
0
ferrostatin-1
0
Phenylenediamines
0
NF-E2-Related Factor 2
0
Phospholipid Hydroperoxide Glutathione Peroxidase
EC 1.11.1.12
NFE2L2 protein, human
0
SLC7A11 protein, human
0
Iron
E1UOL152H7
Amino Acid Transport System y+
0
Receptors, Transferrin
0
Piperazines
0
erastin
0
Actins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e17551Informations de copyright
©2024 Yang et al.
Déclaration de conflit d'intérêts
The authors declare there are no competing interests.
Références
Adv Wound Care (New Rochelle). 2022 Apr;11(4):192-201
pubmed: 34498914
Int J Med Sci. 2021 Jul 25;18(15):3361-3366
pubmed: 34522161
Front Neurosci. 2020 Apr 21;14:267
pubmed: 32372896
Blood. 2020 Aug 6;136(6):726-739
pubmed: 32374849
Biomed Pharmacother. 2023 Sep;165:115185
pubmed: 37487441
Redox Biol. 2022 Nov;57:102509
pubmed: 36302319
Ugeskr Laeger. 2022 Jun 20;184(25):
pubmed: 35781362
Front Cell Dev Biol. 2020 May 26;8:360
pubmed: 32528951
Aging (Albany NY). 2020 Jan 12;12(1):844-865
pubmed: 31929114
J Inflamm Res. 2022 Jun 27;15:3689-3708
pubmed: 35783244
Biomolecules. 2021 Jul 23;11(8):
pubmed: 34439762
Medicina (Kaunas). 2021 Jul 19;57(7):
pubmed: 34357011
Arch Dermatol Res. 2023 Sep;315(7):1887-1896
pubmed: 36781457
Exp Dermatol. 2021 Jan;30(1):146-161
pubmed: 32479693
Clin Exp Dermatol. 2022 Mar;47(3):507-515
pubmed: 34480483
Int J Clin Exp Pathol. 2020 Aug 01;13(8):2041-2049
pubmed: 32922599
Biomed Pharmacother. 2020 Sep;129:110287
pubmed: 32540643
Biochim Biophys Acta Mol Basis Dis. 2021 Dec 1;1867(12):166204
pubmed: 34175430
Int J Dermatol. 2021 Jun;60(6):661-671
pubmed: 32905614
DNA Cell Biol. 2019 Jul;38(7):725-733
pubmed: 31140862
Front Immunol. 2020 Dec 04;11:603187
pubmed: 33343575
J Transl Med. 2021 Aug 26;19(1):367
pubmed: 34446045
Front Immunol. 2022 Aug 03;13:940645
pubmed: 35990663
Mol Cancer. 2023 Jul 17;22(1):113
pubmed: 37461104
Ann Transl Med. 2022 Mar;10(6):368
pubmed: 35434035
Free Radic Biol Med. 2019 Mar;133:46-54
pubmed: 29969719
Redox Biol. 2021 Oct;46:102131
pubmed: 34530349
Mol Med Rep. 2022 Aug;26(2):
pubmed: 35703358
Acta Biochim Biophys Sin (Shanghai). 2022 Dec 25;54(12):1-9
pubmed: 36514215
Front Aging Neurosci. 2024 Jan 11;16:1309115
pubmed: 38282692
Cell Death Differ. 2022 Oct;29(10):1982-1995
pubmed: 35383293
Photodiagnosis Photodyn Ther. 2023 Jun;42:103612
pubmed: 37220842
Oxid Med Cell Longev. 2022 Oct 12;2022:7686956
pubmed: 36275899
Int J Mol Sci. 2018 Mar 02;19(3):
pubmed: 29498630
Cell Death Dis. 2020 Feb 3;11(2):88
pubmed: 32015325
Front Physiol. 2023 Aug 17;14:1205771
pubmed: 37664432
Semin Plast Surg. 2021 Aug;35(3):145-152
pubmed: 34526861
Plast Reconstr Surg. 2022 Jan 1;149(1):79e-94e
pubmed: 34813576