m6A-driven epigenetic dysregulation of the tyrosine phosphatase PTPN14 promotes psoriasis progression via YAP signaling

Summary: Abstract Body: Psoriasis, a chronic and incurable inflammatory skin disease, poses significant clinical challenges due to its hallmark features of excessive keratinocyte proliferation and persistent inflammation. Despite advances in understanding psoriasis pathogenesis, the precise molecular mechanisms remain incompletely defined. Here, we identify non-receptor protein tyrosine phosphatase 14 (PTPN14), a tumor suppressor known for its role in cellular proliferation and differentiation, as a novel regulator in psoriasis. Analysis of the GEO database and single-cell RNA sequencing demonstrated significantly reduced PTPN14 expression in keratinocytes from psoriatic lesions compared to healthy skin. These results were confirmed by RT-qPCR and immunofluorescence in psoriatic patients and an imiquimod (IMQ)-induced psoriasis-like mouse model. Functional studies revealed that silencing PTPN14 in vivo, via topical application of small interfering RNA, exacerbated IMQ-induced psoriasis-like dermatitis. In vitro experiments showed that PTPN14 knockdown in human keratinocytes impaired cell differentiation while driving hyperproliferation by activating the YAP signaling pathway. Further investigation into the upstream regulation of PTPN14 uncovered a critical role for m6A methylation. m6A methylation sequencing identified reduced m6A-modified PTPN14 mRNA in psoriatic epidermis in mice, and loss of m6A methyltransferase METTL3 in keratinocytes further suppressed PTPN14 expression. These findings highlight m6A-driven epigenetic dysregulation as a key mechanism underlying PTPN14 downregulation in psoriasis. Collectively, this study unveils a novel m6A-YAP axis involving PTPN14, linking epigenetic dysregulation to keratinocyte hyperproliferation and impaired differentiation in psoriasis. These insights not only deepen our understanding of psoriasis pathogenesis but also identify PTPN14 as a promising therapeutic target for innovative treatment strategies. Yu Zhuang^{1, 2}, Lian Cui^{1, 2}, Yuling Shi^{1, 2}, Chunyuan Guo^{1, 2} 1. Department of Dermatology, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, China. 2. Institute of Psoriasis, Tongji University School of Medicine, Shanghai, China. Genetic Disease, Gene Regulation, Gene Therapy & Epigenetics