TUDCA was identified as a potential therapeutic drug for nonalcoholic steatohepatitis complicated with hypercholesterolemia targeting ADRA2C by integrated bioinformatics and experimental verification
- 1School of Basic Medicine, Mudanjiang Medical University, Mudanjiang, 157011 China
- 2College of Life Science, Mudanjiang Medical University, Mudanjiang, 157011 China
- 3School of Basic Medicine, Qiqihar Medical University, Qiqihar, 161006 China
Abstract
Nonalcoholic steatohepatitis (NASH) is a type of liver disease in which fat accumulates in the liver with inflammation. Hypercholesterolemia is a common autosomal dominant inherited metabolic disease. Previous studies have suggested a potential association between NASH and hypercholesterolemia, but the pathophysiological mechanisms were unclear. Bioinformatics analysis identified four core comorbidity genes (ADRA2C, IL27RA, LDB3, SF3A2). Molecular docking showed that TUDCA had the lowest binding affinity with ADRA2C and formed a stable hydrogen bond network. In vitro experiments demonstrated that TUDCA reverses PA/OA-induced high expression of ADRA2C. The cell thermal shift assay confirmed that TUDCA can directly bind to ADRA2C and enhance its thermal stability. Mechanistically, overexpression of ADRA2C significantly weakened the activation effect of TUDCA on the cGMP-PKG pathway and the recovery effect of downstream VASP phosphorylation. In vivo experiments showed that TUDCA dose-dependently improved liver function indicators infiltration in the two mice models, and inhibited the expression of core genes in liver tissue and restored the level of p-VASP protein. This research reveals the co-pathogenesis of NASH and hypercholesterolemia. These common hub genes and candidate drug may provide new targets for further mechanistic research as well as new therapies for patients with NASH and hypercholesterolemia.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s13062-026-00926-w.
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BibTeX
@article{liu2026tudca,
title = {{TUDCA was identified as a potential therapeutic drug for nonalcoholic steatohepatitis complicated with hypercholesterolemia targeting ADRA2C by integrated bioinformatics and experimental verification}},
author = {Hongfeng Liu and Yuxiao Fan and Zhanpeng Sun and Shuai Yuan and Biao Li and Jing Mi and Shengnan Lv and Jiajun Yang and Yihao Zhai and Qi Yuan},
journal = {Biology Direct},
year = {2026},
month = aug,
doi = {10.1186/s13062-026-00926-w},
url = {https://doi.org/10.1186/s13062-026-00926-w},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - TUDCA was identified as a potential therapeutic drug for nonalcoholic steatohepatitis complicated with hypercholesterolemia targeting ADRA2C by integrated bioinformatics and experimental verification
AU - Hongfeng Liu
AU - Yuxiao Fan
AU - Zhanpeng Sun
AU - Shuai Yuan
AU - Biao Li
AU - Jing Mi
AU - Shengnan Lv
AU - Jiajun Yang
AU - Yihao Zhai
AU - Qi Yuan
PY - 2026
DA - 2026/08/08
JO - Biology Direct
DO - 10.1186/s13062-026-00926-w
UR - https://doi.org/10.1186/s13062-026-00926-w
AB - Nonalcoholic steatohepatitis (NASH) is a type of liver disease in which fat accumulates in the liver with inflammation. Hypercholesterolemia is a common autosomal dominant inherited metabolic disease. Previous studies have suggested a potential association between NASH and hypercholesterolemia, but the pathophysiological mechanisms were unclear. Bioinformatics analysis identified four core comorbidity genes (ADRA2C, IL27RA, LDB3, SF3A2). Molecular docking showed that TUDCA had the lowest binding affinity with ADRA2C and formed a stable hydrogen bond network. In vitro experiments demonstrated that TUDCA reverses PA/OA-induced high expression of ADRA2C. The cell thermal shift assay confirmed that TUDCA can directly bind to ADRA2C and enhance its thermal stability. Mechanistically, overexpression of ADRA2C significantly weakened the activation effect of TUDCA on the cGMP-PKG pathway and the recovery effect of downstream VASP phosphorylation. In vivo experiments showed that TUDCA dose-dependently improved liver function indicators infiltration in the two mice models, and inhibited the expression of core genes in liver tissue and restored the level of p-VASP protein. This research reveals the co-pathogenesis of NASH and hypercholesterolemia. These common hub genes and candidate drug may provide new targets for further mechanistic research as well as new therapies for patients with NASH and hypercholesterolemia. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s13062-026-00926-w.
SN - 1745-6150
ER -