Choline kinase beta promotes psoriasis pathogenesis by regulating sphingolipid metabolism and activating the PI3K/Akt/GSK3β signaling pathway.

Psoriasis is a chronic inflammatory skin disorder characterized by dysregulated lipid metabolism, yet the key molecular drivers remain unclear. This study aimed to identify and validate novel metabolic regulators in psoriasis. Using a multi-stage bioinformatics analysis of public datasets with three machine learning algorithms, Choline Kinase Beta (CHKB) was identified as a key upregulated gene strongly associated with sphingolipid metabolism. This finding was validated in clinical samples, where CHKB expression was significantly elevated in psoriatic lesions compared to healthy controls. To investigate its functional role, CHKB was knocked down in an imiquimod-induced psoriasis mouse model and a cytokine-stimulated keratinocyte model. In vivo, CHKB knockdown ameliorated disease severity, reducing epidermal hyperproliferation, inflammation, and oxidative stress. In vitro, silencing CHKB inhibited keratinocyte hyperproliferation, induced G1 cell cycle arrest, and suppressed the secretion of pro-inflammatory cytokines. Mechanistically, CHKB knockdown altered sphingolipid metabolism, increasing ceramide levels, and concurrently inhibited the activation of the pro-survival PI3K/Akt/GSK3β signaling pathway in both models. Furthermore, a rescue experiment confirmed that the pro-psoriatic effects of CHKB overexpression in keratinocytes were dependent on this metabolic pathway, as they were reversed by the sphingolipid synthesis activator 4-HPR. Collectively, these findings establish that CHKB promotes psoriasis pathogenesis by regulating sphingolipid metabolism and activating PI3K/Akt/GSK3β signaling, highlighting it as a novel therapeutic target.