Cuproptosis Facilitates Chronic Skin Inflammation by Regulating the α‐Ketoglutarate/H3K4me3/Ferritin Heavy Chain 1 Signaling Pathway‐Mediated Ferroptosis Article Swipe
Pian Yu
,
Kaixuan Li
,
S. Luo
,
Rongxuan Yan
,
Xiaoqing Yi
,
Chi Fang
,
Sihui Ma
,
Guanming Wang
,
Fanyan Luo
,
Xiang Chen
,
Cong Peng
,
Jie Li
·
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1002/mco2.70425
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1002/mco2.70425
Dysregulated copper homeostasis is implicated in inflammatory skin diseases such as psoriasis and atopic dermatitis (AD), but the role of cuproptosis remains poorly defined. This study aimed to elucidate the role and mechanism of cuproptosis in inflammatory skin diseases. Transcriptome analysis of patient lesions revealed significant alterations in cuproptosis‐related genes correlating with disease‐specific pathological features. These cuproptosis‐related gene expression signatures demonstrated strong clinical relevance to therapeutic efficacy in both psoriasis and AD cohorts. Functional validation using disease models showed that pharmacologically inhibiting cuproptosis with the copper chelator tetrathiomolybdate (TTM), or genetically knocking down the copper importer SLC31A1, effectively alleviated chronic skin inflammation and hallmark pathological changes induced by imiquimod (IMQ) or calcipotriol (MC903). Mechanistically, we uncovered that SLC31A1‐mediated cuproptosis promotes intracellular α‐ketoglutarate (α‐KG) accumulation, driving activation of the lysine demethylase KDM5B. Activated KDM5B specifically demethylates H3K4me3 marks at the promoter of the ferroptosis regulator ferritin heavy chain 1 (FTH1), suppressing its transcription and consequently sensitizing keratinocytes to ferroptotic cell death, thereby amplifying inflammatory tissue damage. Our findings establish a fundamental pathogenic SLC31A1/KDM5B/FTH1 molecular axis linking dysregulated copper metabolism and cuproptosis to ferroptosis execution in psoriasis and AD, providing significant mechanistic insights and pinpointing promising therapeutic targets for these refractory skin disorders.
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- Language
- en
- Landing Page
- https://doi.org/10.1002/mco2.70425
- https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/mco2.70425
- OA Status
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- References
- 62
- OpenAlex ID
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Cuproptosis Facilitates Chronic Skin Inflammation by Regulating the α‐Ketoglutarate/H3K4me3/Ferritin Heavy Chain 1 Signaling Pathway‐Mediated FerroptosisWork title
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articleOpenAlex work type
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enPrimary language
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2025Year of publication
- Publication date
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2025-10-01Full publication date if available
- Authors
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Pian Yu, Kaixuan Li, S. Luo, Rongxuan Yan, Xiaoqing Yi, Chi Fang, Sihui Ma, Guanming Wang, Fanyan Luo, Xiang Chen, Cong Peng, Jie LiList of authors in order
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https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/mco2.70425Direct OA link when available
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| publication_date | 2025-10-01 |
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| referenced_works | https://openalex.org/W1997854913, https://openalex.org/W1973480138, https://openalex.org/W1926541489, https://openalex.org/W3185553375, https://openalex.org/W1971326367, https://openalex.org/W1876035649, https://openalex.org/W4221115671, https://openalex.org/W2052977681, https://openalex.org/W2947042837, https://openalex.org/W1969822551, https://openalex.org/W2997801268, https://openalex.org/W1992069947, https://openalex.org/W4385144619, https://openalex.org/W2008810664, https://openalex.org/W4386468218, https://openalex.org/W2604389567, https://openalex.org/W3080367034, https://openalex.org/W3006169882, https://openalex.org/W3192687721, https://openalex.org/W3005233576, https://openalex.org/W3158401813, https://openalex.org/W3033109150, https://openalex.org/W2118480909, https://openalex.org/W2312279372, https://openalex.org/W2892288216, https://openalex.org/W2523439769, https://openalex.org/W3144245775, https://openalex.org/W3162305544, https://openalex.org/W3210506738, https://openalex.org/W4381308037, https://openalex.org/W4377565280, https://openalex.org/W4309604216, https://openalex.org/W4311873428, https://openalex.org/W4377042029, https://openalex.org/W4366828822, https://openalex.org/W4289731102, https://openalex.org/W4289890715, https://openalex.org/W4285012525, https://openalex.org/W4297226808, https://openalex.org/W3076758593, https://openalex.org/W3194058374, https://openalex.org/W4379232415, https://openalex.org/W4381033612, https://openalex.org/W4381164556, https://openalex.org/W4380871394, https://openalex.org/W4381470044, https://openalex.org/W4386084423, https://openalex.org/W4377023104, https://openalex.org/W4391878282, https://openalex.org/W2952112680, https://openalex.org/W4404572842, https://openalex.org/W4404869036, https://openalex.org/W4402322087, https://openalex.org/W4401371352, https://openalex.org/W4402025848, https://openalex.org/W2466781195, https://openalex.org/W1530657831, https://openalex.org/W1967868572, https://openalex.org/W2120102274, https://openalex.org/W4315435482, https://openalex.org/W4377966863, https://openalex.org/W4387095456 |
| referenced_works_count | 62 |
| abstract_inverted_index.1 | 148 |
| abstract_inverted_index.a | 169 |
| abstract_inverted_index.AD | 72 |
| abstract_inverted_index.as | 11 |
| abstract_inverted_index.at | 138 |
| abstract_inverted_index.by | 108 |
| abstract_inverted_index.in | 6, 36, 48, 68, 184 |
| abstract_inverted_index.is | 4 |
| abstract_inverted_index.of | 20, 34, 42, 127, 141 |
| abstract_inverted_index.or | 90, 111 |
| abstract_inverted_index.to | 28, 65, 157, 181 |
| abstract_inverted_index.we | 115 |
| abstract_inverted_index.AD, | 187 |
| abstract_inverted_index.Our | 166 |
| abstract_inverted_index.and | 13, 32, 71, 103, 153, 179, 186, 192 |
| abstract_inverted_index.but | 17 |
| abstract_inverted_index.for | 197 |
| abstract_inverted_index.its | 151 |
| abstract_inverted_index.the | 18, 30, 85, 94, 128, 139, 142 |
| abstract_inverted_index.This | 25 |
| abstract_inverted_index.axis | 174 |
| abstract_inverted_index.both | 69 |
| abstract_inverted_index.cell | 159 |
| abstract_inverted_index.down | 93 |
| abstract_inverted_index.gene | 58 |
| abstract_inverted_index.role | 19, 31 |
| abstract_inverted_index.skin | 8, 38, 101, 200 |
| abstract_inverted_index.such | 10 |
| abstract_inverted_index.that | 80, 117 |
| abstract_inverted_index.with | 52, 84 |
| abstract_inverted_index.(AD), | 16 |
| abstract_inverted_index.(IMQ) | 110 |
| abstract_inverted_index.KDM5B | 133 |
| abstract_inverted_index.These | 56 |
| abstract_inverted_index.aimed | 27 |
| abstract_inverted_index.chain | 147 |
| abstract_inverted_index.genes | 50 |
| abstract_inverted_index.heavy | 146 |
| abstract_inverted_index.marks | 137 |
| abstract_inverted_index.study | 26 |
| abstract_inverted_index.these | 198 |
| abstract_inverted_index.using | 76 |
| abstract_inverted_index.(TTM), | 89 |
| abstract_inverted_index.KDM5B. | 131 |
| abstract_inverted_index.atopic | 14 |
| abstract_inverted_index.copper | 2, 86, 95, 177 |
| abstract_inverted_index.death, | 160 |
| abstract_inverted_index.lysine | 129 |
| abstract_inverted_index.models | 78 |
| abstract_inverted_index.poorly | 23 |
| abstract_inverted_index.showed | 79 |
| abstract_inverted_index.strong | 62 |
| abstract_inverted_index.tissue | 164 |
| abstract_inverted_index.(FTH1), | 149 |
| abstract_inverted_index.H3K4me3 | 136 |
| abstract_inverted_index.changes | 106 |
| abstract_inverted_index.chronic | 100 |
| abstract_inverted_index.damage. | 165 |
| abstract_inverted_index.disease | 77 |
| abstract_inverted_index.driving | 125 |
| abstract_inverted_index.induced | 107 |
| abstract_inverted_index.lesions | 44 |
| abstract_inverted_index.linking | 175 |
| abstract_inverted_index.patient | 43 |
| abstract_inverted_index.remains | 22 |
| abstract_inverted_index.targets | 196 |
| abstract_inverted_index.thereby | 161 |
| abstract_inverted_index.(MC903). | 113 |
| abstract_inverted_index.ABSTRACT | 0 |
| abstract_inverted_index.SLC31A1, | 97 |
| abstract_inverted_index.analysis | 41 |
| abstract_inverted_index.chelator | 87 |
| abstract_inverted_index.clinical | 63 |
| abstract_inverted_index.cohorts. | 73 |
| abstract_inverted_index.defined. | 24 |
| abstract_inverted_index.diseases | 9 |
| abstract_inverted_index.efficacy | 67 |
| abstract_inverted_index.ferritin | 145 |
| abstract_inverted_index.findings | 167 |
| abstract_inverted_index.hallmark | 104 |
| abstract_inverted_index.importer | 96 |
| abstract_inverted_index.insights | 191 |
| abstract_inverted_index.knocking | 92 |
| abstract_inverted_index.promoter | 140 |
| abstract_inverted_index.promotes | 120 |
| abstract_inverted_index.revealed | 45 |
| abstract_inverted_index.(α‐KG) | 123 |
| abstract_inverted_index.Activated | 132 |
| abstract_inverted_index.diseases. | 39 |
| abstract_inverted_index.elucidate | 29 |
| abstract_inverted_index.establish | 168 |
| abstract_inverted_index.execution | 183 |
| abstract_inverted_index.features. | 55 |
| abstract_inverted_index.imiquimod | 109 |
| abstract_inverted_index.mechanism | 33 |
| abstract_inverted_index.molecular | 173 |
| abstract_inverted_index.promising | 194 |
| abstract_inverted_index.providing | 188 |
| abstract_inverted_index.psoriasis | 12, 70, 185 |
| abstract_inverted_index.regulator | 144 |
| abstract_inverted_index.relevance | 64 |
| abstract_inverted_index.uncovered | 116 |
| abstract_inverted_index.Functional | 74 |
| abstract_inverted_index.activation | 126 |
| abstract_inverted_index.alleviated | 99 |
| abstract_inverted_index.amplifying | 162 |
| abstract_inverted_index.dermatitis | 15 |
| abstract_inverted_index.disorders. | 201 |
| abstract_inverted_index.expression | 59 |
| abstract_inverted_index.implicated | 5 |
| abstract_inverted_index.inhibiting | 82 |
| abstract_inverted_index.metabolism | 178 |
| abstract_inverted_index.pathogenic | 171 |
| abstract_inverted_index.refractory | 199 |
| abstract_inverted_index.signatures | 60 |
| abstract_inverted_index.validation | 75 |
| abstract_inverted_index.alterations | 47 |
| abstract_inverted_index.correlating | 51 |
| abstract_inverted_index.cuproptosis | 21, 35, 83, 119, 180 |
| abstract_inverted_index.demethylase | 130 |
| abstract_inverted_index.effectively | 98 |
| abstract_inverted_index.ferroptosis | 143, 182 |
| abstract_inverted_index.ferroptotic | 158 |
| abstract_inverted_index.fundamental | 170 |
| abstract_inverted_index.genetically | 91 |
| abstract_inverted_index.homeostasis | 3 |
| abstract_inverted_index.mechanistic | 190 |
| abstract_inverted_index.pinpointing | 193 |
| abstract_inverted_index.sensitizing | 155 |
| abstract_inverted_index.significant | 46, 189 |
| abstract_inverted_index.suppressing | 150 |
| abstract_inverted_index.therapeutic | 66, 195 |
| abstract_inverted_index.Dysregulated | 1 |
| abstract_inverted_index.calcipotriol | 112 |
| abstract_inverted_index.consequently | 154 |
| abstract_inverted_index.demethylates | 135 |
| abstract_inverted_index.demonstrated | 61 |
| abstract_inverted_index.dysregulated | 176 |
| abstract_inverted_index.inflammation | 102 |
| abstract_inverted_index.inflammatory | 7, 37, 163 |
| abstract_inverted_index.pathological | 54, 105 |
| abstract_inverted_index.specifically | 134 |
| abstract_inverted_index.Transcriptome | 40 |
| abstract_inverted_index.accumulation, | 124 |
| abstract_inverted_index.intracellular | 121 |
| abstract_inverted_index.keratinocytes | 156 |
| abstract_inverted_index.transcription | 152 |
| abstract_inverted_index.Mechanistically, | 114 |
| abstract_inverted_index.pharmacologically | 81 |
| abstract_inverted_index.SLC31A1/KDM5B/FTH1 | 172 |
| abstract_inverted_index.SLC31A1‐mediated | 118 |
| abstract_inverted_index.disease‐specific | 53 |
| abstract_inverted_index.tetrathiomolybdate | 88 |
| abstract_inverted_index.α‐ketoglutarate | 122 |
| abstract_inverted_index.cuproptosis‐related | 49, 57 |
| cited_by_percentile_year | |
| corresponding_author_ids | https://openalex.org/A5059847326, https://openalex.org/A5100441899, https://openalex.org/A5023743448, https://openalex.org/A5100392758 |
| countries_distinct_count | 2 |
| institutions_distinct_count | 12 |
| corresponding_institution_ids | https://openalex.org/I139660479, https://openalex.org/I4210115624, https://openalex.org/I4210159865 |
| citation_normalized_percentile.value | 0.63968842 |
| citation_normalized_percentile.is_in_top_1_percent | False |
| citation_normalized_percentile.is_in_top_10_percent | False |