This study investigates shared molecular mechanisms between pyoderma gangrenosum (PG) and inflammatory bowel disease (IBD) and systematically evaluates the therapeutic potential of JAK inhibitors targeting this pathway. Despite the clear clinical comorbidity, the core inflammatory pathways driving cross-tissue associations between the two diseases remain unclear. Furthermore, systematic mechanistic evidence is lacking regarding whether JAK inhibitors act by regulating shared pathological pathways in patients with comorbidities. To address this, this study integrated PG skin and IBD intestinal transcriptome data, single-cell transcriptomic data, and genome-wide association study (GWAS) meta-data from public databases. It employed a multi-level computational biology approach combining Mendelian randomization, weighted gene co-expression network analysis, protein interaction network construction, molecular docking simulations, and system dynamics modeling. The results revealed that genetic analysis confirmed IBD as a causal risk factor for PG, precisely identifying six shared genetic loci. Transcriptomic analysis identified a cross-tissue conserved inflammatory module centered on the JAK-STAT pathway, with JAK2 and STAT3 identified as network hubs. Molecular docking predicted high affinity of baricitinib for both JAK1 and JAK2, while system dynamics modeling demonstrated that its intervention effectively suppresses signaling in the shared inflammatory network. This study reveals the molecular basis of the “gut–skin axis” comorbidity between PG and IBD from a multi-omics integration perspective. It provides predictive computational evidence for the use of JAK inhibitors in targeted comorbidity therapy. Baricitinib is identified as a particularly promising candidate. These findings advance the transition from empirical drug use to mechanism-guided precision treatment strategies. Although this study provides multiscale computational simulation evidence, the lack of direct experimental validation of these predicted results necessitates further confirmation through in vitro and in vivo experiments.
Yao et al. (Wed,) studied this question.