Folate alleviated skin inflammation and fibrosis resulting from impaired homocysteine metabolism
Skin fibrosis, characterized by uncontrolled secretion of extracellular matrix (ECM) proteins such as collagen, can lead to excessive scarring and compromised tissue function. Despite the widespread occurrence of fibrotic diseases, effective therapies are lacking. Recent clinical studies have demons...
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Elsevier
2025-03-01
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| Series: | Redox Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S221323172500014X |
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| author | Jiefeng Huang Wuyan Lu Shenli Zhao Zixin Cai Linxiao Li Zihao Hu Yu Jiang Jinyi Deng Yiming Tang Chenzhang Shi Chen Wang Guangpeng Liu Shuaijun Li |
| author_facet | Jiefeng Huang Wuyan Lu Shenli Zhao Zixin Cai Linxiao Li Zihao Hu Yu Jiang Jinyi Deng Yiming Tang Chenzhang Shi Chen Wang Guangpeng Liu Shuaijun Li |
| author_sort | Jiefeng Huang |
| collection | DOAJ |
| description | Skin fibrosis, characterized by uncontrolled secretion of extracellular matrix (ECM) proteins such as collagen, can lead to excessive scarring and compromised tissue function. Despite the widespread occurrence of fibrotic diseases, effective therapies are lacking. Recent clinical studies have demonstrated a positive correlation between serum homocysteine (Hcy) levels and the severity of systemic sclerosis. However, it remains unclear whether Hcy accumulation plays a pathogenic role in skin fibrosis. Here, we report that Hcy metabolism in fibroblasts plays a crucial role in regulating the pathogenesis of skin fibrosis. Fibrotic skin fibroblasts exhibited elevated levels of Hcy due to the downregulation of catabolism genes CBS and MTR. Experimental skin fibrosis was induced and exacerbated in mouse skin fibroblasts and tissues through adenoviral knockdown of Cbs or Mtr, whereas overexpression of these catabolic genes mitigated the pathogenesis. Furthermore, exogenous Hcy supplementation induced and aggravated the expression of inflammatory and fibrotic genes, promoting both spontaneous and BLM-induced skin fibrosis. Notably, folate administration enhanced Hcy catabolism and ameliorated skin inflammation and fibrosis by inhibiting JAK2/STAT3 signaling pathway. Collectively, these results indicate that skin fibrosis is associated with Hcy metabolic disorders and suggest that targeting Hcy metabolism or supplementing folate may provide a novel strategy for skin fibrosis. |
| format | Article |
| id | doaj-art-823abb8efb1544b992ed81bd1cdbbe0c |
| institution | Kabale University |
| issn | 2213-2317 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj-art-823abb8efb1544b992ed81bd1cdbbe0c2025-02-07T04:47:30ZengElsevierRedox Biology2213-23172025-03-0180103501Folate alleviated skin inflammation and fibrosis resulting from impaired homocysteine metabolismJiefeng Huang0Wuyan Lu1Shenli Zhao2Zixin Cai3Linxiao Li4Zihao Hu5Yu Jiang6Jinyi Deng7Yiming Tang8Chenzhang Shi9Chen Wang10Guangpeng Liu11Shuaijun Li12Department of Plastic Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, ChinaDepartment of Plastic Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, ChinaThe First Affiliated Hospital of Wannan Medical College, Yijishan Hospital of Wannan Medical College, Anhui, 241001, ChinaDepartment of Plastic Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, ChinaDepartment of Gastrointestinal Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, ChinaDepartment of Plastic Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, ChinaDepartment of Gastrointestinal Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, ChinaDepartment of Gastrointestinal Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, ChinaDepartment of Gastrointestinal Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, ChinaDepartment of Gastrointestinal Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China; Corresponding author. Tongji University School of Medicine, Shanghai, China.Department of Plastic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China; Corresponding author. Tongji University School of Medicine, Shanghai, China.Department of Plastic Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China; Corresponding author. Tongji University School of Medicine, Shanghai, China.Department of Plastic Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China; Corresponding author. Tongji University School of Medicine, Shanghai, China.Skin fibrosis, characterized by uncontrolled secretion of extracellular matrix (ECM) proteins such as collagen, can lead to excessive scarring and compromised tissue function. Despite the widespread occurrence of fibrotic diseases, effective therapies are lacking. Recent clinical studies have demonstrated a positive correlation between serum homocysteine (Hcy) levels and the severity of systemic sclerosis. However, it remains unclear whether Hcy accumulation plays a pathogenic role in skin fibrosis. Here, we report that Hcy metabolism in fibroblasts plays a crucial role in regulating the pathogenesis of skin fibrosis. Fibrotic skin fibroblasts exhibited elevated levels of Hcy due to the downregulation of catabolism genes CBS and MTR. Experimental skin fibrosis was induced and exacerbated in mouse skin fibroblasts and tissues through adenoviral knockdown of Cbs or Mtr, whereas overexpression of these catabolic genes mitigated the pathogenesis. Furthermore, exogenous Hcy supplementation induced and aggravated the expression of inflammatory and fibrotic genes, promoting both spontaneous and BLM-induced skin fibrosis. Notably, folate administration enhanced Hcy catabolism and ameliorated skin inflammation and fibrosis by inhibiting JAK2/STAT3 signaling pathway. Collectively, these results indicate that skin fibrosis is associated with Hcy metabolic disorders and suggest that targeting Hcy metabolism or supplementing folate may provide a novel strategy for skin fibrosis.http://www.sciencedirect.com/science/article/pii/S221323172500014XSkin fibrosisInflammationHomocysteineFolateJAK2/STAT3 signaling pathway |
| spellingShingle | Jiefeng Huang Wuyan Lu Shenli Zhao Zixin Cai Linxiao Li Zihao Hu Yu Jiang Jinyi Deng Yiming Tang Chenzhang Shi Chen Wang Guangpeng Liu Shuaijun Li Folate alleviated skin inflammation and fibrosis resulting from impaired homocysteine metabolism Redox Biology Skin fibrosis Inflammation Homocysteine Folate JAK2/STAT3 signaling pathway |
| title | Folate alleviated skin inflammation and fibrosis resulting from impaired homocysteine metabolism |
| title_full | Folate alleviated skin inflammation and fibrosis resulting from impaired homocysteine metabolism |
| title_fullStr | Folate alleviated skin inflammation and fibrosis resulting from impaired homocysteine metabolism |
| title_full_unstemmed | Folate alleviated skin inflammation and fibrosis resulting from impaired homocysteine metabolism |
| title_short | Folate alleviated skin inflammation and fibrosis resulting from impaired homocysteine metabolism |
| title_sort | folate alleviated skin inflammation and fibrosis resulting from impaired homocysteine metabolism |
| topic | Skin fibrosis Inflammation Homocysteine Folate JAK2/STAT3 signaling pathway |
| url | http://www.sciencedirect.com/science/article/pii/S221323172500014X |
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