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Liquid biopsy is a very powerful tool because it is rapid and non-invasive. In fact, AST and ALT are known to be very good biomarkers of liver damage; however, it is difficult to distinguish the cause of liver damage or the status of the liver only on the basis of elevated levels of AST and ALT. Thus, in some cases further examination is needed for detailed lesion assessment. Recently, using EV-associated miRNAs or circulating free miRNAs in serum as biomarkers has made it possible to diagnose thirteen types of cancer with an accuracy of 90% or more (Ogata-Kawata et al. 2014; Shimomura et al. 2016; Yokoi et al. 2018; Yao et al. 2019; Asano et al. 2019; Shiino et al. 2019; Usuba et al. 2019; Asakura et al. 2020). The development of next-generation toxicity tests using miRNA as a biomarker is therefore expected.

Our studies identified forty-two novel miRNAs—such as miR-122 and miR-192—as candidate liver damage biomarkers. Using these novel biomarkers, it may be possible to elucidate the mechanism of hepatotoxicity caused by the administration of drugs or chemical substances other than carbon tetrachloride. Since EVs in blood are secreted by a wide variety of cells, it is necessary to clarify the origin of the EV-associated miRNAs. In addition to their utility as markers of hepatotoxicity, EV-associated miRNAs are expected to be valuable as biomarkers of toxicity that targets other organs, such as the kidney, the lung, and the heart.

Although this study analyzed the effects of carbon tetrachloride administration at a single time point, twenty-four hours, evaluating the time courses of biomarkers in response to the repeated administration of carbon tetrachloride may be applicable if we want to shorten chronic toxicity tests and long-term carcinogenicity tests.

It may also be important to elucidate the function of the identified EV-associated miRNAs induced by hepatotoxicity in vivo.