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

  • J Adv Res. 2026 Apr 14:S2090-1232(26)00343-7. doi: 10.1016/j.jare.2026.04.039.
Yixin Luo  1 ,  Xiaolei Su  1 ,  Chen Zhang  1 ,  Zhenhua Liu  1 ,  Kang Li  1 ,  Pei Qiao  1 ,  Chencan Su  1 ,  Chunying Xiao  1 ,  Xia Li  1 ,  Jiaoling Chen  1 ,  Lei Wang  1 ,  Weinan Guo  1 ,  Erle Dang  2 ,  Gang Wang  3 ,  Bing Li  4
Affiliations
  • 1. Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
  • 2. Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China. Electronic address: [email protected].
  • 3. Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China. Electronic address: [email protected].
  • 4. Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China. Electronic address: [email protected].
PMID: 41985670 DOI: 10.1016/j.jare.2026.04.039
Abstract

Introduction: Psoriasis is a chronic inflammatory disease characterized by epidermal hyperplasia and dermal T cell infiltration. Epidermal keratinocytes function not only as the primary targets of the inflammatory response but also play a pivotal role in initiating and maintaining the inflammatory state. Sirtuin 7 (SIRT7), an NAD+-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: Expression of SIRT family members was evaluated in lesions from psoriasis patients. Afterward, the effects of SIRT7 on psoriasis were investigated utilizing an imiquimod-induced psoriasis-like mouse model with KRT5cre; SIRT7fl/fl 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.

Keywords
Hypoxia-inducible factor 1-alpha deacetylation; Hypoxia-inducible factor 1-alpha ubiquitination; Keratinocyte glycolysis; Psoriasis; Sirtuin 7.
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