New biomarkers of liver injury are required in the clinic and in preclinical pharmaceutical evaluation. Previous studies demonstrate that two liver-enriched microRNAs (miR-122 and miR-192) are promising biomarkers of acetaminophen-induced acute liver injury (APAP-ALI) in mice. We have examined these molecules, for the first time, in humans with APAP poisoning. Serum miR-122 and miR-192 were substantially higher in APAP-ALI patients, compared to healthy controls (median DDCt [25th, 75th percentile]) (miR-122: 1,265 [491, 4,270] and -192 were substantially higher in APAP-ALI patients than CKD patients (miR-122: P < 0.0001; miR-192: P < 0.0004). miR-122 correlated with peak ALT levels in the APAP-ALI cohort (Pearson R 5 0.46, P 5 0.0005), but not with prothrombin time. miR-122 was also raised alongside peak ALT levels in a group of patients with non-APAP ALI. Day 1 serum miR-122 levels were almost 2-fold higher in APAP-ALI patients who satisfied King's College Criteria (KCC), compared to those who did not satisfy KCC, although this did not reach statistical significance (P 5 0.15). Conclusion: This work provides the first evidence for the potential use of miRNAs as biomarkers of human drug-induced liver injury. (HEPATOLOGY 2011;54:1767-1776 T he development of informative biomarkers of drug-induced liver injury (DILI) remains a primary aim in clinical and preclinical settings. The challenge is to develop biomarkers that are stable, that can be rapidly and accurately quantified in standard hospital laboratories, are minimally invasive, tissue specific, and add true diagnostic/prognostic value to detect and monitor the level of a pathogenic insult to the liver.1 The current battery of available biomarkers to assess liver integrity includes circulating protein markers of hepatocellular injury, such as the aminotransferases, markers of liver functional impairment, such as prothrombin time, markers of blood chemistry, and a number of novel mechanistic biomarkers of tissue injury (e.g., cytokeratin-18 and high-mobility group box-1 protein). 2 Deficiencies discovered with current blood-based biomarkers include the unacceptable frequency of false positives/negatives, poor

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Cellular senescence is a mechanism that provides an irreversible barrier to cell cycle progression to prevent undesired proliferation. However, under pathological circumstances, senescence can adversely affect organ function, viability and regeneration. We have developed a mouse model of biliary senescence, based on the conditional deletion of Mdm2 in bile ducts under the control of the Krt19 promoter, that exhibits features of biliary disease. Here we report that senescent cholangiocytes induce profound alterations in the cellular and signalling microenvironment, with recruitment of myofibroblasts and macrophages causing collagen deposition, TGFβ production and induction of senescence in surrounding cholangiocytes and hepatocytes. Finally, we study how inhibition of TGFβ-signalling disrupts the transmission of senescence and restores liver function. We identify cellular senescence as a detrimental mechanism in the development of biliary injury. Our results identify TGFβ as a potential therapeutic target to limit senescence-dependent aggravation in human cholangiopathies.