Authors
Dan Wang, Jian Chen, Wei Xu, Sachin Mulmi Shrestha, Qin Lu, Lihua Ren, Qinghua Ji, Hailu Wu, Ruihua Shi
Published in
Molecular medicine (Cambridge, Mass.). Volume 32. Issue 1. Aug 06, 2026. Epub Aug 06, 2026.
Abstract
Gastric intestinal metaplasia (GIM), a precancerous lesion and risk factor for gastric cancer, is closely associated with chronic bile acid (BA) exposure; however, its molecular mechanisms remain unclear. This study aimed to identify key regulators involved in BA-associated GIM and to elucidate their functional roles.
TRIM15 and GIM markers (CDX2, MUC2, KLF4, and VIL1) were assessed in human GIM and paired normal tissues by RNA-seq, RT‒qPCR, Western blotting (WB), and immunofluorescence (IF). BA profiles were analyzed using UHPLC‒MS/MS. In vitro, GES-1 cells were treated with CDCA and subjected to TRIM15 gain- and loss-of-function assays. CDX2-mediated transcriptional regulation of TRIM15 was evaluated by dual-luciferase reporter and ChIP assays. NF-κB signaling and related proteins were assessed by WB and IF. The interaction between TRIM15 and IκBα and the levels of ubiquitination were investigated by coimmunoprecipitation, LC-MS/MS and protein-protein docking analysis. Functional assays were used to assess proliferation and apoptosis. In vivo validation was performed using an AAV9-mediated TRIM15 knockdown rat model.
TRIM15 expression was consistently upregulated in GIM and increased stepwise with disease severity, accompanied by a positive association with CDX2 expression. BA profiling revealed the selective enrichment of cholic acid (CA) and chenodeoxycholic acid (CDCA), which induced GIM-associated phenotypes in vitro. Mechanistically, CDX2 directly bound to the TRIM15 promoter to increase its transcription, whereas TRIM15 promoted CDX2 expression via the NF-κB pathway, resulting in the formation of a regulatory loop. Further mechanistic analyses revealed that TRIM15 promoted K48-linked ubiquitination and subsequent proteasomal degradation of IκBα, thereby enhancing p65 phosphorylation. Notably, this effect was abolished by expression of the degradation-resistant IκBα S32A/S36A mutant. In vivo, TRIM15 knockdown attenuated gastric mucosal injury and intestinal metaplasia and reduced NF-κB signaling and CDX2 expression.
These findings suggest the involvement of a TRIM15-NF-κB-CDX2 regulatory loop in BA-associated GIM. TRIM15 may contribute to epithelial reprogramming under BA exposure and could be a potential biomarker and therapeutic target for GIM progression.
PMID:
42870234
Bibliographic data and abstract were imported from PubMed on 14 Oct 2026.
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