Bibliographic Details
| Title: |
S1PR3-driven positive feedback loop sustains STAT3 activation and keratinocyte hyperproliferation in psoriasis |
| Authors: |
Panpan Lian, Li Li, Renwei Lu, Bin Zhang, Junaid Wazir, Chaode Gu, Bojie Ma, Wenyuan Pu, Wangsen Cao, Zhiqiang Huang, Zhonglan Su, Hongwei Wang |
| Source: |
Cell Death and Disease, Vol 16, Iss 1, Pp 1-14 (2025) |
| Publisher Information: |
Nature Publishing Group, 2025. |
| Publication Year: |
2025 |
| Collection: |
LCC:Cytology |
| Subject Terms: |
Cytology, QH573-671 |
| More Details: |
Abstract Psoriasis is a chronic inflammatory skin disorder characterized by hyperproliferation of keratinocytes and persistent inflammation. Although persistent activation of signal transducer and activator of transcription 3 (STAT3) is implicated in its pathogenesis, the mechanisms underlying the sustained STAT3 activation remain poorly understood. Here, we identify sphingosine-1-phosphate receptor 3 (S1PR3) as a critical regulator of STAT3 activation and psoriasis pathogenesis, orchestrating a self-amplifying circuit that sustains keratinocyte hyperproliferation and chronic inflammation. S1PR3 expression is markedly elevated in psoriatic lesions and correlates with disease severity. Using genetic and pharmacological approaches, we reveal a novel S1PR3–Src–STAT3 signaling axis that drives both early and prolonged STAT3 activation in keratinocytes. Mechanistically, S1PR3 operates through Gαi/PKA-mediated Src activation, enhancing STAT3 phosphorylation and subsequent transcriptional activity. Importantly, we reveal a previously unrecognized positive feedback loop wherein activated STAT3 directly upregulates S1PR3 expression, perpetuating inflammation and hyperproliferation. Genetic deletion of S1pr3 in mice or pharmacological inhibition of S1PR3 significantly attenuates psoriasis-like skin inflammation, decreasing epidermal hyperplasia, dermal angiogenesis, and inflammatory mediator production. These findings provide new insights into the molecular mechanisms underlying psoriasis and identify S1PR3 as a promising therapeutic target. Our study suggests that disrupting the S1PR3–STAT3 feedback loop may offer a novel strategy for treating psoriasis and potentially other chronic inflammatory diseases driven by persistent STAT3 activation. |
| Document Type: |
article |
| File Description: |
electronic resource |
| Language: |
English |
| ISSN: |
2041-4889 |
| Relation: |
https://doaj.org/toc/2041-4889 |
| DOI: |
10.1038/s41419-025-07358-w |
| Access URL: |
https://doaj.org/article/d3caade375034d27bddb19d97e607558 |
| Accession Number: |
edsdoj.3caade375034d27bddb19d97e607558 |
| Database: |
Directory of Open Access Journals |
