Small RNA Sequencing of Circulating microRNAs Reveals Novel Biomarkers

Drug-induced liver injury (DILI) is a leading cause of acute liver failure and the major reason for withdrawal of drugs from the market. Preclinical evaluation of drug candidates has failed to detect about 40% of potentially hepatotoxic compounds in humans. At the onset of liver injury in humans, currently used biomarkers have difficulty differentiating severe DILI from mild, and/or predict the outcome of injury for individual subjects. Therefore, new biomarker approaches for predicting and diagnosing DILI in humans are urgently needed. Recently, circulating microRNAs (miRNAs) such as miR-122 and miR-192 have emerged as promising biomarkers of liver injury in preclinical species and in DILI patients.

In this study, researchers from Maastricht University focused on examining global circulating miRNA profiles in serum samples from subjects with liver injury caused by accidental acetaminophen (APAP) overdose. Upon applying next generation high-throughput sequencing of small RNA libraries, they identified 36 miRNAs, including 3 novel miRNA-like small nuclear RNAs, which were enriched in the serum of APAP overdosed subjects. The set comprised miRNAs that are functionally associated with liver-specific biological processes and relevant to APAP toxic mechanisms. Although more patients need to be investigated, this study suggests that profiles of circulating miRNAs in human serum might provide additional biomarker candidates and possibly mechanistic information relevant to liver injury.


Pearson clustering of miRNAs with other biomarkers. Clustering is based on Pearson correlation that was calculated using serum levels of miRNAs or protein concentration/activity values of classical and emerging biomarkers of DILI across all 24 samples.

Krauskopf J, Caiment F, Claessen SM, Johnson KJ, Warner RL, Schomaker SJ, Burt DA, Aubrecht J, Kleinjans JC. (2014) Application of High-Throughput Sequencing to Circulating microRNAs Reveals Novel Biomarkers for Drug-induced Liver Injury. Toxicol Sci [Epub ahead of print]. [abstract]

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