Lee Chae Won, Kang Eun Seok, Jeong Seogsong, Han Hyun Wook
Department of Biomedical Informatics, CHA University School of Medicine, Seongnam, Republic of Korea.
Department of Biomedical Informatics, Korea University College of Medicine, Seoul, Republic of Korea.
PLoS One. 2025 Jun 4;20(6):e0323880. doi: 10.1371/journal.pone.0323880. eCollection 2025.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major risk factor for liver cirrhosis, yet effective prevention or treatment strategies remain limited. To address this, we utilized a signature-based in silico drug repositioning approach to identify potential therapeutics for MASLD that may reduce the risk of cirrhosis.
We analyzed gene expression datasets to identify differentially expressed genes (DEGs) in MASLD and matched them to candidate drugs using L1000CDS2. We further validated potential drugs by cross-referencing with prescription data from the Korea National Health Insurance Service (NHIS). Participants who underwent health screenings between 2013 and 2014 were included. MASLD was diagnosed in individuals with hepatic steatosis (fatty liver index ≥60) and at least one cardiometabolic risk factor.
We identified 11 drug candidates and analyzed 49,555 MASLD patients (mean age: 63.0 years, SD: 8.6). Atenolol (SHR: 0.81; 95% CI: 0.72-0.92; P < 0.001), isosorbide dinitrate (SHR: 0.82; 95% CI: 0.73-0.93; P = 0.001), and valsartan (SHR: 0.52; 95% CI: 0.45-0.60; P < 0.001) were associated with a reduced risk of cirrhosis. Conversely, amlodipine-based combinations (SHR: 1.24; 95% CI: 1.11-1.39; P < 0.001), torasemide (SHR: 1.39; 95% CI: 1.24-1.56; P < 0.001), and valsartan-based combinations (SHR: 1.22; 95% CI: 1.09-1.37; P < 0.001) were linked to an increased risk.
Our findings suggest that antihypertensive drugs such as atenolol and isosorbide dinitrate may protect MASLD patients from cirrhosis, providing valuable insights for clinical applications and treatment strategies.
This study is limited to drugs registered in the Korean NHIS, potentially excluding other relevant candidates. Additionally, the absence of dietary and genetic data in the NHIS database may introduce residual confounding. Lastly, as the study population consists solely of Korean adults, the findings may not be generalizable to other populations.
代谢功能障碍相关脂肪性肝病（MASLD）是肝硬化的主要危险因素，但有效的预防或治疗策略仍然有限。为解决这一问题，我们采用基于特征的计算机药物重新定位方法来识别可能降低肝硬化风险的MASLD潜在治疗药物。
我们分析基因表达数据集以识别MASLD中差异表达基因（DEGs），并使用L1000CDS2将它们与候选药物进行匹配。我们通过与韩国国民健康保险服务（NHIS）的处方数据交叉参考进一步验证潜在药物。纳入了2013年至2014年间接受健康筛查的参与者。MASLD在肝脂肪变性（脂肪肝指数≥60）且至少有一种心脏代谢危险因素的个体中被诊断出来。
我们识别出11种候选药物，并分析了49555例MASLD患者（平均年龄：63.0岁，标准差：8.6）。阿替洛尔（标准化风险比：0.81；95%置信区间：0.72 - 0.92；P < 0.001）、硝酸异山梨酯（标准化风险比：0.82；95%置信区间：0.73 - 0.93；P = 0.001）和缬沙坦（标准化风险比：0.52；95%置信区间：0.45 - 0.60；P < 0.001）与肝硬化风险降低相关。相反，氨氯地平类组合（标准化风险比：1.24；95%置信区间：1.11 - 1.39；P < 0.001）、托拉塞米（标准化风险比：1.39；95%置信区间：1.24 - 1.56；P < 0.001）和缬沙坦类组合（标准化风险比：1.22；95%置信区间：1.09 - 1.37；P < 0.001）与风险增加相关。
我们的研究结果表明，阿替洛尔和硝酸异山梨酯等降压药物可能保护MASLD患者免于肝硬化，为临床应用和治疗策略提供了有价值的见解。
本研究仅限于在韩国NHIS注册的药物，可能排除了其他相关候选药物。此外，NHIS数据库中缺乏饮食和遗传数据可能会引入残余混杂因素。最后，由于研究人群仅由韩国成年人组成，研究结果可能无法推广到其他人群。
