Sirtuin 7-mediated deacetylation of hypoxia-inducible factor 1-alpha facilitates glycolytic reprogramming and inflammation of keratinocytes in psoriasis

INTRODUCTION: -dependent protein deacetylase, is critical for various cellular processes, including proliferation, metabolic homeostasis, and inflammation. However, its role in psoriasis remains elusive. OBJECTIVES: To investigate the role of SIRT7 in psoriasis pathogenesis and its underlying mechanism. METHODS: and cellular models involving siRNA transfection or overexpression through plasmid. The deacetylation target of SIRT7 was elucidated in vitro analyses, including identification of SIRT7 substrates, validation of deacetylation sites via site-specific acetylation-mimetic and null mutants. RESULTS: Among the SIRT family members, the expression of SIRT7 was significantly increased in the epidermal keratinocytes of patients with psoriasis compared to healthy controls. This finding was confirmed using an imiquimod-induced psoriasis-like mouse model, where SIRT7 deficiency in keratinocytes alleviated the psoriatic phenotype. In vitro studies revealed that SIRT7 contributes to keratinocyte proliferation, the expression of inflammatory cytokines, and glycolytic processes. Furthermore, we identified hypoxia-inducible factor 1-alpha (HIF-1α) as a novel substrate of SIRT7, which undergoes deacetylation at lysine 674 (K674). The deacetylated form of HIF-1α exhibited enhanced K63-linked polyubiquitination while reducing K48-linked ubiquitination, thereby avoiding proteasomal degradation and maintaining stability through interaction with ubiquitin-specific peptidase 9 x-linked (USP9X). CONCLUSION: Our findings reveal a novel SIRT7-HIF-1α signaling pathway that regulates keratinocyte metabolism, proliferation, and inflammation, which is involved in promoting psoriasis progression. This finding identifies a potential therapeutic target for psoriasis management.