Inhibition of PI3K rebalanced Th1/Th17/Treg and restored macrophage function in imiquimod-induced psoriasis.

Psoriasis is a chronic immune-mediated skin disease with unmet therapeutic needs. Dysregulated Th1/Th17/Treg cells and M1 macrophage polarization contribute to its pathogenesis, while PI3K/Akt pathway activation is implicated in psoriatic lesions. This study investigated the therapeutic potential of selective PI3Kδ (CAL-101) and PI3Kγ (AS-605240) inhibitors, alone or combined, using imiquimod-induced psoriatic mice. CAL-101 monotherapy significantly outperformed AS-605240 and combination therapy in mitigating weight loss, splenomegaly, and key histopathological features (hyperkeratosis, acanthosis, inflammatory infiltration). Mechanistically, CAL-101 effectively suppressed PI3K/Akt phosphorylation in skin lesions and restored T-cell homeostasis by rebalancing Th1/Th2/Th17 ratios and enhancing Treg frequency. Conversely, combination therapy paradoxically increased Th17 cells and showed antagonistic effects. Both monotherapies maintained macrophage phagocytic function and suppressed M1 markers (e.g., NOS2, CCL20). While both inhibitors elevated caspase-1, only CAL-101 increased caspase-11; combination therapy uniquely triggered gasdermin D (GSDMD) -mediated pyroptosis. All regimens reversed aberrant MCP-1 upregulation, though CAL-101 was less effective. These findings highlight the superior efficacy of PI3Kδ-specific inhibition over PI3Kγ targeting or dual inhibition in alleviating psoriatic inflammation and immune dysregulation. CAL-101 shows promise as a potential immunomodulatory agent in preclinical models of psoriasis, warranting further investigation into its mechanisms of action.