Targeting IMPDH2 by Casticin attenuates psoriatic inflammation by suppressing STAT3 activation in keratinocytes

Psoriasis is a chronic immune-mediated inflammatory disease. Inosine Monophosphate Dehydrogenase 2 (IMPDH2), the rate-limiting enzyme in de novo guanine nucleotide biosynthesis, is upregulated during cytokine-mediated inflammatory responses, yet its specific role in keratinocyte biology and psoriatic pathogenesis remains unexplored. Here, we identify IMPDH2 as a critical metabolic regulator of psoriatic inflammation. Integrated analysis of bulk and single-cell RNA sequencing datasets revealed consistent upregulation of IMPDH2 in psoriatic keratinocytes, which was further validated by immunofluorescence staining of patient skin biopsies. In an imiquimod (IMQ)-induced murine psoriasis model, pharmacological inhibition of IMPDH2 with Casticin attenuated disease progression and alleviated epidermal inflammation. Mechanistically, IMPDH2 promotes keratinocyte inflammation through GTP-dependent activation of STAT3 signaling: IMPDH2 knockdown or inhibition reduced STAT3 phosphorylation and suppressed inflammatory responses, effects that were reversed by exogenous GTP supplementation, whereas IMPDH2 overexpression enhanced STAT3 phosphorylation and inflammation. Supporting a direct causal link between IMPDH2 and STAT3, the STAT3 activator colivelin reversed the effect of IMPDH2 inhibition, while the STAT3 inhibitor Stattic abrogated the effect of IMPDH2 overexpression. Collectively, this study establishes a previously unrecognized IMPDH2-GTP-STAT3 axis driving keratinocyte inflammation and nominates Casticin as a promising therapeutic candidate for psoriasis.