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Abstract

Here, we investigated the role of protein tyrosine phosphatase nonreceptor type 2 (PTPN2) in psoriasis pathogenesis, focusing on its regulation of the stimulator of interferon genes–signal transducer and activator of transcription 3 (STING–STAT3)-autophagy axis. Using cellular and imiquimod-induced mouse models, we assessed PTPN2 expression and function using multiple techniques, including immunofluorescence, co-immunoprecipitation, and Western blotting. A significant downregulation of PTPN2 expression was observed in psoriatic tissues. We established that PTPN2 directly interacts with STING and regulates its phosphorylation, with direct evidence from catalytic-dead PTPN2 mutant experiments showing that PTPN2's dephosphorylation of STING is activity-dependent. PTPN2 overexpression curbed keratinocyte proliferation, stimulated apoptosis and autophagy, and reduced the secretion of proinflammatory cytokines, such as tumor necrosis factor-alpha, interleukin (IL) 23 subunit alpha (A), and IL-17A. The application of a STING agonist mitigated these effects, whereas STAT3 inhibition restored them. PTPN2 overexpression attenuated psoriatic pathology, and this therapeutic benefit was further enhanced by co-administering the autophagy inducer rapamycin. Collectively, our results delineate a novel mechanism by which PTPN2 alleviates psoriasis-like pathology in keratinocytes by targeting the STING–STAT3 pathway and promoting autophagy and apoptosis. These findings indicate that PTPN2 is a potential therapeutic target, with in vivo validation supporting its translational relevance.