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Objective Guselkumab (GUS) is a dual-acting IL-23p19 inhibitor that neutralises IL-23 and binds to CD64. GUS intravenous (IV) induction and subcutaneous (SC) maintenance was effective in patients (pts) with moderate to severe UC (QUASAR). Week 12 (W12) results from ASTRO showed efficacy of GUS SC induction in UC. Molecular changes are presented.Methods At baseline (BL), 418 pts with moderate to severe UC were randomized 2:1 to GUS 400mg SC or placebo (PBO). Molecular analysis compared induction W12 to BL. Transcriptional profiling of colonic biopsies from 339 pts was performed with bulk RNA sequencing. A comparative analysis was done with biopsies previously analyzed from 593 pts from the QUASAR Phase 3 induction study. Genes and gene co-expression modules were evaluated for differential expression. Correlation between Geboes scores and transcriptional gene module changes were evaluated in colonic biopsies from 413 pts. Molecular changes were assessed in the context of clinical remission and histologic and endoscopic mucosal improvement (HEMI) at W12. Serum IL-22 proteomic profiling of 355 pts was conducted using a high-sensitivity IL-22 assay.Results GUS SC induction downregulated inflammatory transcriptional modules in colon tissue at W12, representing Th17, IFNG signaling, inflamed epithelium, plasma cell, neutrophil and inflammatory fibroblast biology, and upregulated healthy epithelium-related gene modules including goblet cells and healthy epithelium (all false discovery rate [FDR]<0.05). Response to GUS SC induction significantly correlated with changes in transcriptional gene modules with GUS 200mg IV induction in QUASAR (r=0.98, p<0.0001). Pts with clinical remission at W12 had the most robust changes in gene module expression from BL (p<0.0001), nearing non-IBD control levels, compared to non-remitters. Similar results seen in pts who achieved HEMI at W12. Subgroup analyses by prior BIO/JAKi/S1Pi treatment showed similar magnitude of changes in both treatment-naïve and -resistant groups (R=0.93, p<0.0001). Serum IL-22 significantly decreased at W12 (p<0.05) with GUS SC, similar to IL-22 changes observed with GUS IV induction. Similar changes were seen for tissue IL-22 gene expression (p<0.05) nearing non-IBD control levels at W12. Pts in clinical remission at W12 had a robust decrease in Geboes total scores (p<0.05) compared to non-remitters.Conclusion Mechanistic observations confirm that GUS SC and GUS IV induction treatment show significant correlation, supporting the efficacy of both routes of administration in UC. Results from molecular analysis of ASTRO corroborate efficacy results for GUS SC induction in UC, with GUS SC induction reducing inflammatory biology towards a normal state while upregulating genes associated with healthy epithelium in pts in clinical remission or HEMI at W12.