SIRT6 Aggravates Psoriasiform Skin Inflammation Through Modulation of the SOCS2-STAT1/3 Pathway.

To investigate the role and molecular mechanisms of the deacetylase SIRT6 in psoriasis and evaluate its potential as a therapeutic target for topical treatment. The expression of SIRT6 in psoriatic lesions and healthy skin was analyzed using datasets from the GEO database. In vitro, Human Immortalized Epidermal Cells (HaCaT) were stimulated with TNF-α to establish a psoriasis-like cellular model. SIRT6 was overexpressed or knocked down in HaCaT cells to evaluate its effects on keratinocyte inflammation, proliferation, and migration. Integrated transcriptomic analysis and subsequent validation were conducted to explore the signaling pathways regulated by SIRT6. Changes in mRNA expression, protein levels and inflammatory cytokine secretion were assessed by RT-qPCR, Western blotting, immunohistochemistry, and ELISA. Therapeutic potential was assessed using a SIRT6 inhibitor-loaded alginate/carbomer hydrogel in an imiquimod-induced psoriasiform dermatitis mouse model and in human psoriatic skin explants ex vivo. GEO dataset analysis revealed that SIRT6 expression was significantly higher in psoriatic lesions than in either healthy controls or non-lesional skin (both p < 0.0001) and significantly decreased after treatment with biologic agents or JAK inhibitors (p < 0.05 vs pre-treatment). In HaCaT cells, TNF‑α stimulation upregulated SIRT6 by 1.5-fold (p <0.01). Overexpression of SIRT6 enhanced TNF-α-induced production of pro-inflammatory cytokines (IL-6, IL-23, and TNF-α) and the alarmins S100A8 and S100A9, while promoting keratinocyte proliferation and migration, whereas SIRT6 knockdown produced opposite effects. Combined transcriptomic profiling and multiple validation assays (qPCR, Western blot, and immunohistochemistry) revealed that SIRT6 overexpression activated the STAT signaling pathway by downregulating SOCS2 and upregulating STAT1/3 phosphorylation, while SIRT6 knockdown or inhibition yielded the opposite outcomes. Topical administration of the SIRT6 inhibitor-loaded hydrogel alleviated imiquimod-induced psoriasiform dermatitis in mice and reduced inflammatory responses in human psoriatic skin explants. SIRT6 exacerbates psoriasiform inflammation by modulating the SOCS2-STAT1/3 signaling pathway. These findings suggest that topical inhibition of SIRT6 may represent a potential therapeutic strategy for psoriasis.