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

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.