银屑病是一种常见且反复发作的炎症性皮肤病，其特征为炎症细胞浸润真皮、表皮细胞的过度增殖、凋亡减少和异常的角质形成。本研究中，我们发现一种重要的甲基转移酶G9A，在银屑病患者的病变部位和咪唑啉病变模型中高表达。过去的研究表明，G9A通过调控凋亡、增殖、分化和侵袭等方式参与各种肿瘤的发病机制。然而，G9A在银屑病等皮肤炎症性疾病中的作用尚不清楚。到目前为止，我们的数据显示，G9A抑制剂BIX01294的局部使用以及角质形成细胞特异性G9A的敲除首次极大地缓解了IMQ诱导的银屑病变。在机制上，G9A的缺失导致Ectodysplasin A受体（EDAR）的下调，从而抑制了NF-κB通路的激活，进而导致角质形成细胞增殖减少和凋亡增加，因此改善了由IMQ引起的银屑病皮炎。总的来说，我们展示了抑制G9A通过调控细胞增殖和凋亡而改善银屑病状皮炎，主要是通过调节细胞增殖和凋亡而不是炎症过程，并且这种分子可能被视为角质形成细胞过度增殖性疾病如银屑病的潜在治疗靶点。© 2023. 作者。

Psoriasis is a common and recurrent inflammatory skin disease characterized by inflammatory cells infiltration of the dermis and excessive proliferation, reduced apoptosis, and abnormal keratosis of the epidermis. In this study, we found that G9A, an important methyltransferase that mainly mediates the mono-methylation (me1) and di-methylation (me2) of histone 3 lysine 9 (H3K9), is highly expressed in lesions of patients with psoriasis and imiquimod (IMQ)-induced psoriasis-like mouse model. Previous studies have shown that G9A is involved in the pathogenesis of various tumors by regulating apoptosis, proliferation, differentiation, and invasion. However, the role of G9A in skin inflammatory diseases such as psoriasis remains unclear. Our data so far suggest that topical administration of G9A inhibitor BIX01294 as well as keratinocyte-specific deletion of G9A greatly alleviated IMQ-induced psoriatic alterations in mice for the first time. Mechanistically, the loss function of G9A causes the downregulation of Ectodysplasin A receptor (EDAR), consequently inhibiting the activation of NF-κB pathway, resulting in impaired proliferation and increased apoptosis of keratinocytes, therefore ameliorating the psoriatic dermatitis induced by IMQ. In total, we show that inhibition of G9A improves psoriatic-like dermatitis mainly by regulating cell proliferation and apoptosis rather than inflammatory processes, and that this molecule may be considered as a potential therapeutic target for keratinocyte hyperproliferative diseases such as psoriasis.© 2023. The Author(s).