GSK-2795039

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.

Oxidative stress is a pivotal driver of epileptogenesis and seizure-induced neuronal pathology, with NADPH oxidase 2 (NOX2) serving as a major source of reactive oxygen species (ROS) in the brain. Despite its established role in seizure pathophysiology, the therapeutic implications of selective NOX2 inhibition in epilepsy remain insufficiently explored. Here, we investigate the effect of GSK2795039, a potent NOX2 inhibitor, using both in vitro and in vivo epilepsy models. In vitro, mixed cortical neuroglial cultures were treated with 4-aminopyridine (4-AP) and picrotoxin (PTX) to induce epileptiform activity. Calcium imaging and dihydroethidium (DHE) fluorescence assays revealed that GSK2795039 significantly reduced synchronous Ca²⁺ oscillations and ROS accumulation. In vivo, adult rats implanted with ECoG transmitters were pretreated with GSK2795039 prior to pentylenetetrazol (PTZ) administration to evoke seizures. ECoG recording and behavioral seizure scoring showed that GSK2795039 pretreatment inhibited the seizure severity, duration and cumulative seizure burden. Molecular analyses, including quantitative PCR and western blotting, revealed a significant downregulation of NOX2 mRNA in both the hippocampus and cortex, although protein levels remained unchanged. Additionally, immunofluorescence and histological staining confirmed that GSK2795039 mitigated oxidative DNA damage, preserved hippocampal neuronal integrity, and differentially modulated pro- and anti-inflammatory cytokine expression. These findings underscore NOX2 inhibition as a compelling neuroprotective strategy and highlight the potential of GSK2795039 to suppress oxidative and inflammatory cascades in epilepsy. Targeting NOX2 may represent a promising avenue for precision therapeutics in oxidative stress-driven epilepsy.