2. Academic Validation
  3. p67phox/NOX2 inhibits psoriasis by regulating the HIF-1α-glycolysis axis via p53-AMPK in keratinocytes

p67phox/NOX2 inhibits psoriasis by regulating the HIF-1α-glycolysis axis via p53-AMPK in keratinocytes

  • Free Radic Biol Med. 2025 Sep:237:503-514. doi: 10.1016/j.freeradbiomed.2025.06.016.
Ang Li 1,  Zhou Zhuang 2,  Qingyue Xia 1,  Xinzhu Zhou 2,  Jungang Yang 2,  Baoyi Liu 3,  Xiaoyi Huang 4,  Ke Xue 5,  Xuejiao Song 6,  Jingkai Xu 7,  Yong Cui 8
Affiliations

Affiliations

  • 1 Department of Dermatology, China-Japan Friendship Hospital, Beijing, China; Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
  • 2 Department of Dermatology, China-Japan Friendship Hospital, Beijing, China; Peking University China-Japan Friendship School of Clinical Medicine Department of Dermatology, China-Japan Friendship Hospital, Beijing, China.
  • 3 Changhai Hospital, The Second Military Medical University, Shanghai, China.
  • 4 Institute of Dermatology and Department of Dermatology of the First Affiliated Hospital, Anhui Medical University, Hefei, China.
  • 5 Department of Dermatology, China-Japan Friendship Hospital, Beijing, China.
  • 6 Department of Dermatology, China-Japan Friendship Hospital, Beijing, China. Electronic address: xuejiaojolly@126.com.
  • 7 Department of Dermatology, China-Japan Friendship Hospital, Beijing, China. Electronic address: jkaixu1992@163.com.
  • 8 Department of Dermatology, China-Japan Friendship Hospital, Beijing, China. Electronic address: wuhucuiyong@vip.163.com.
PMID: 40516795 DOI: 10.1016/j.freeradbiomed.2025.06.016
Abstract

Psoriasis is a chronic inflammatory skin disorder characterized by keratinocyte hyperproliferation, oxidative stress, and metabolic reprogramming. While Reactive Oxygen Species (ROS) are implicated in skin inflammation, their cellular sources and regulatory mechanisms in psoriatic pathophysiology remain poorly defined. Here, we identify p67phox/NOX2, a critical ROS-generating enzyme, as a key regulator of glucose metabolism in psoriatic keratinocytes. p67phox/NOX2 expression was significantly upregulated in psoriatic epidermis and positively correlated with glycolysis and JAK-STAT signaling signatures. p67phox knockdown in keratinocytes disrupted metabolic homeostasis, leading to AMPK inactivation, p53 suppression, and HIF-1α stabilization. These perturbations triggered increased lactate production, metabolic lactylation, and proinflammatory cytokine expression. In an imiquimod-induced murine psoriasis model, pharmacologic inhibition of NOX2 by GSK2795039 aggravated psoriasiform inflammation, whereas BML-111, a lipoxin A4 analog, alleviated pathology by restoring p67phox/NOX2 activity and metabolic balance. Together, NOX2-derived ROS function in the protective metabolism of epidermal inflammation, and that therapeutic activation, rather than inhibition, of NOX2 may represent a novel strategy for the treatment of psoriasis.

Keywords

Glycolysis; HIF-1α; Inflammation; NOX2; Psoriasis; Reactive oxygen species.

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