Title:Relief of EGFR/FOS-downregulated miR-103a by loganin alleviates NF-kappaB-triggered inflammation and gut barrier disruption in colitis

Abstract:Due to the ever-rising global incidence rate of inflammatory bowel disease (IBD) and the lack of effective clinical treatment drugs, elucidating the detailed pathogenesis, seeking novel targets, and developing promising drugs are the top priority for IBD treatment. Here, we demonstrate that the levels of microRNA (miR)-103a were significantly downregulated in the inflamed mucosa of ulcerative colitis (UC) patients, along with elevated inflammatory cytokines (IL-1beta/TNF-alpha) and reduced tight junction protein (Occludin/ZO-1) levels, as compared with healthy control objects. Consistently, miR-103a deficient intestinal epithelial cells Caco-2 showed serious inflammatory responses and increased permeability, and DSS induced more severe colitis in miR-103a-/- mice than wild-type ones. Mechanistic studies unraveled that c-FOS suppressed miR-103a transcription via binding to its promoter, then miR-103a-targeted NF-kappaB activation contributes to inflammatory responses and barrier disruption by targeting TAB2 and TAK1. Notably, the traditional Chinese medicine Cornus officinalis (CO) and its core active ingredient loganin potently mitigated inflammation and barrier disruption in UC by specifically blocking the EGFR/RAS/ERK/c-FOS signaling axis, these effects mainly attributed to modulated miR-103a levels as the therapeutic activities of them were almost completely shielded in miR-103a KO mice. Taken together, this work reveals that loganin relieves EGFR/c-FOS axis-suppressed epithelial miR-103a expression, thereby inhibiting NF-kappaB pathway activation, suppressing inflammatory responses, and preserving tight junction integrity in UC. Thus, our data enrich mechanistic insights and promising targets for UC treatment.