Biochimica et biophysica acta. Molecular basis of disease · 2026
TNFAIP1 as a novel therapeutic target in ulcerative colitis and salidroside as its potential inhibitor.
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Ouyang Qi, Tian Shengye, Jiang Hong, Li Moyong, Zeng Yuteng, Zhao Linhui, Zhou Fang, Xiang Shuanglin, Hu Xiang
Аннотация
BACKGROUND: The absence of known inhibitors for TNFAIP1, a TNF-α-induced protein, has limited its exploration as a therapeutic target for ulcerative colitis (UC). This study aimed to validate TNFAIP1's pathogenic role in UC and to identify the first direct TNFAIP1-targeting compound from natural compounds.
METHODS: We integrated bioinformatics analysis, DSS-induced colitis models in Tnfaip1-knockout mice, and virtual screening to identify Salidroside as a potential TNFAIP1-targeting compound. Cellular thermal shift and ubiquitination assays confirmed its direct interaction with TNFAIP1 and its effect on protein stability. Oral administration of Salidroside ameliorated colitis in wild-type mice, phenocopying the protective effect of Tnfaip1 deficiency.
RESULTS: TNFAIP1 was significantly upregulated in UC patients and colitic mice. Tnfaip1-knockout conferred profound resistance to colitis, mechanistically linked to the suppression of the IKK/IκB/NF-κB pathway, modulation of CREB signaling, and restoration of a beneficial gut microbiota. Based on this target validation, virtual screening identified Salidroside as a top candidate. Crucially, Salidroside administration in wild-type mice phenocopied the protective effects of genetic knockout, alleviating disease severity and downregulating the TNFAIP1-driven inflammatory network. CETSA confirmed a direct physical interaction between Salidroside and TNFAIP1.
CONCLUSION: This study validates TNFAIP1 as a key pathogenic driver of UC and identifies Salidroside as a first-in-class direct TNFAIP1-targeting compound with therapeutic potential.
METHODS: We integrated bioinformatics analysis, DSS-induced colitis models in Tnfaip1-knockout mice, and virtual screening to identify Salidroside as a potential TNFAIP1-targeting compound. Cellular thermal shift and ubiquitination assays confirmed its direct interaction with TNFAIP1 and its effect on protein stability. Oral administration of Salidroside ameliorated colitis in wild-type mice, phenocopying the protective effect of Tnfaip1 deficiency.
RESULTS: TNFAIP1 was significantly upregulated in UC patients and colitic mice. Tnfaip1-knockout conferred profound resistance to colitis, mechanistically linked to the suppression of the IKK/IκB/NF-κB pathway, modulation of CREB signaling, and restoration of a beneficial gut microbiota. Based on this target validation, virtual screening identified Salidroside as a top candidate. Crucially, Salidroside administration in wild-type mice phenocopied the protective effects of genetic knockout, alleviating disease severity and downregulating the TNFAIP1-driven inflammatory network. CETSA confirmed a direct physical interaction between Salidroside and TNFAIP1.
CONCLUSION: This study validates TNFAIP1 as a key pathogenic driver of UC and identifies Salidroside as a first-in-class direct TNFAIP1-targeting compound with therapeutic potential.