丝氨酸代谢对肿瘤发生和免疫应答至关重要。腺苷甲硫氨酸（SAM）作为甲基供体通常来源于丝氨酸驱动的单碳代谢。然而，丝氨酸代谢在银屑病皮肤炎症中的参与作用仍不清楚。为了调查丝氨酸代谢与银屑病皮肤炎症的关联，我们收集了银屑病患者的临床样本，并评估了丝氨酸生物合成酶的表达。我们转染了HaCaT人角质细胞系，使用小干扰RNA（siRNA）靶向关键酶或使用抑制剂进行处理。通过RNA测序和DNA甲基化分析，我们阐明了丝氨酸代谢调控的银屑病角质细胞炎症机制。我们建立了咪喹膦（IMQ）诱导的银屑病小鼠模型，以确定SAM治疗对银屑病皮肤炎症的影响。与健康对照组相比，银屑病患者表皮病变中丝氨酸合成途径酶的表达，包括丝氨酸生物合成的第一个速率限制酶磷酸甘油酸脱氢酶（PHGDH），下调。在角质细胞中抑制PHGDH促进了前炎症因子的产生和与银屑病相关的信号通路的富集，包括肿瘤坏死因子α（TNF-α）信号通路、白细胞介素（IL）-17信号通路和NF-κB信号通路。特别是，PHGDH抑制显著促进了角质细胞中六种刺激物（IL-17A，IL-22，IL-1α，巨噬细胞增强子因子2A，TNF-α和肿瘤坏死因子α混合）刺激后IL-6的分泌。机制上，PHGDH抑制通过抑制SAM依赖的DNA甲基化，上调了IL-6的表达，并增加了肌细胞增强因子2A的结合。此外，PHGDH抑制通过SAM抑制增加了NF-κB的活化，从而增加了IL-6的分泌。SAM治疗有效缓解了IMQ诱导的银屑病样皮肤炎症小鼠模型。我们的研究揭示了PHGDH在对抗银屑病皮肤炎症中的关键作用，并指出靶向丝氨酸代谢可能是治疗银屑病的一种新型治疗策略。本文受版权保护。保留所有权利。

Serine metabolism is crucial for tumor oncogenesis and immune responses. S-adenosyl methionine (SAM), a methyl donor, is typically derived from serine-driven one-carbon metabolism. However, the involvement of serine metabolism in psoriatic skin inflammation remains unclear.To investigate the association between serine metabolism and psoriatic skin inflammation.Clinical samples were collected from patients with psoriasis and the expression of serine biosynthesis enzymes was evaluated. The HaCaT human keratinocyte cell line was transfected with small interfering RNA (siRNA) of key enzyme or treated with inhibitors. RNA sequencing and DNA methylation assays were performed to elucidate the mechanisms underlying serine metabolism-regulated psoriatic keratinocyte inflammation An imiquimod (IMQ)-induced psoriasis mouse model was established to determine the effect of the SAM administration on psoriatic skin inflammation.The expression of serine synthesis pathway enzymes, including the first rate-limiting enzyme in serine biosynthesis, phosphoglycerate dehydrogenase (PHGDH), was downregulated in the epidermal lesions of patients with psoriasis compared with that in healthy controls. Suppressing PHGDH in keratinocytes promoted the production of proinflammatory cytokines and enrichment of psoriatic-related signaling pathways, including the tumor necrosis factor-alpha (TNF-α) signaling pathway, interleukin (IL)-17 signaling pathway, and NF-κB signaling pathway. In particular, PHGDH inhibition markedly promoted the secretion of IL-6 in keratinocytes with or without IL-17A, IL-22, IL-1α, oncostatin M, and TNF-α (mix) stimulation. Mechanistically, PHGDH inhibition upregulated the expression of IL-6 by inhibiting SAM-dependent DNA methylation at the promoter and increasing the binding of myocyte enhancer factor 2A. Furthermore, PHGDH inhibition increased the secretion of IL-6 by increasing the activation of NF-κB via SAM inhibition. SAM treatment effectively alleviated IMQ-induced psoriasis-like skin inflammation in mice.Our study revealed the crucial role of PHGDH in antagonizing psoriatic skin inflammation and indicated that targeting serine metabolism may represent a novel therapeutic strategy for treating psoriasis.This article is protected by copyright. All rights reserved.