ADORA3 activation promotes goblet cell differentiation via enhancing HMGCS2-mediated ketogenesis in ulcerative colitis

ADORA3 is mainly expressed in intestinal tract, and has the potential to promote the expression of mucin 2 (MUC2), the function-related factor of goblet cells, under asthma conditions. This study aims to confirm the induction and mechanisms of ADORA3 activation on goblet cells in ulcerative colitis (UC). A significant decrease in ADORA3 expression was found in mucosal biopsies from UC patients and in the colons of colitis mice. This reduction correlated negatively with disease severity and positively with goblet cell number. ADORA3 activation mitigated dextran sulfate sodium (DSS)-induced colitis and facilitated ATOH1-mediated goblet cell differentiation in both in vivo and in vitro. Metabolomics analysis unveiled that ADORA3 activation bolstered ketogenesis, leading to elevated levels of the metabolite BHB. Subsequently, BHB heightened the activity of HDAC1/2, augmenting histone acetylation at the H3K9ac site within the promoter region of the ATOH1 gene. Furthermore, the reason for ADORA3 activation to enhance ketogenesis was attributed to controlling the competitive binding among β-arrestin2, SHP1 and PPARγ. This results in the non-ligand-dependent activation of PPARγ, thereby promoting the transcription of HMGCS2. The exact mechanisms by which ADORA3 promoted goblet cell differentiation and alleviated UC were elucidated using MRS1191 and shHMGCS2 plasmid. Collectively, ADORA3 activation promoted goblet cell differentiation and alleviated UC by enhancing ketogenesis via the "BHB-HDAC1/2-H3K9ac" pathway.