Serine deficiency exacerbates psoriatic skin inflammation by regulating S-adenosyl methionine-dependent DNA methylation and NF-κB signaling activation in keratinocytes

Background 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. Objectives To investigate the association between serine metabolism and psoriatic skin inflammation. Methods 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. Results 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. Conclusions 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.

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