Treatment Of Drug-induced Liver Injury Research Articles

Exploring the efficacy and safety of polyene phosphatidylcholine for treatment of drug-induced liver injury using the Roussel Uclaf causality assessment method: a propensity score matching comparison.

Objective In China, polyene phosphatidylcholine (PPC) is widely used to treat alanine aminotransferase (ALT) elevation associated with various liver diseases. Here, we assessed the efficacy and safety of PPC in treating drug-induced liver injury (DILI).Methods Data from a multicenter retrospective cohort study (DILI-R) were analyzed to compare PPC and magnesium isoglycyrrhizinate (MgIG) for treatment of DILI. We used the Roussel Uclaf causality assessment method (RUCAM) to evaluate patients with DILI. Patients with RUCAM scores ≥6 were included in the study, while those with RUCAM scores <6 were further evaluated by a panel of hepatologists. The primary outcome was the proportion of patients with ALT normalization at discharge. Propensity score matching was used to identify 183 matched pairs of patients (366 patients in total) from 25,927 patients with DILI.Results Among the DILI patients, 64 of 183 (34.97%) achieved normal ALT levels after treatment in both the PPC and the MgIG groups.Conclusion There were no significant differences in safety biomarkers including serum creatinine, blood urea nitrogen, white blood cells, platelets, hemoglobin, and albumin between patients treated with PPC or MgIG. The safety and efficacy of these two agents for treatment of DILI were comparable.

Design, synthesis, and biological evaluation of novel FXR agonists based on auraptene

Farnesoid X receptor (FXR) has been considered as an attractive target for metabolic disorder and liver injury, while many current FXR agonists suffer from undesirable side effects, such as pruritus. Therefore, it is urgent to develop new structure types different from current FXR agonists. In this study, a series of structural optimizations were introduced to displace the unstable coumarin and geraniol scaffolds of auraptene (AUR), a novel and safe FXR agonist. All of these efforts led to the identification of compound 14, a potent FXR agonist with nearly fourfold higher activity than AUR. Molecular modeling study suggested that compound 14 fitted well with binding pocket, and formed the key ionic bond with His291 and Arg328. In acetaminophen-induced acute liver injury model, compound 14 exerts better therapeutic effect than that of AUR, which highlighting its pharmacological potential in the treatment of drug-induced liver injury.

The Study on the Mechanism of Hugan Tablets in Treating Drug-Induced Liver Injury Induced by Atorvastatin.

Atorvastatin is a widely used lipid-lowering drug in the clinic. Research shows that taking long-term atorvastatin has the risk of drug-induced liver injury (DILI) in most patients. Hugan tablets, a commonly used drug for liver disease, can effectively lower transaminase and protect the liver. However, the underlying mechanism of Hugan tablets alleviating atorvastatin-induced DILI remains unclear. To address this problem, comprehensive chemical profiling and network pharmacology methods were used in the study. First, the strategy of “compound−single herb−TCM prescription” was applied to characterize the ingredients of Hugan tablets. Then, active ingredients and potential targets of Hugan tablets in DILI treatment were screened using network pharmacology, molecular docking, and literature research. In the end, the mechanism of Hugan tablets in treating atorvastatin-induced DILI was elucidated. The results showed that Hugan tablets can effectively alleviate DILI induced by atorvastatin in model rats, and 71 compounds were characterized from Hugan tablets. Based on these compounds, 271 potential targets for the treatment of DILI were predicted, and 10 key targets were chosen by characterizing protein–protein interactions. Then, 30 potential active ingredients were screened through the molecular docking with these 10 key targets, and their biological activity was explained based on literature research. Finally, the major 19 active ingredients of Hugan tablets were discovered. In addition, further enrichment analysis of 271 targets indicated that the PI3K-Akt, TNF, HIF-1, Rap1, and FoxO signaling pathways may be the primary pathways regulated by Hugan tablets in treating DILI. This study proved that Hugan tablets could alleviate atorvastatin-induced DILI through multiple components, targets, and pathways.

A narrative review of herb-induced liver injury

: Herb and herbal product have been used for both healthy and specific ailments. Its use as medicine or dietary supplements has increased worldwide for more than a decade due to easy access, purported harmless nature, and perceived therapeutic efficacy. Herb induced liver injury which has been recognized for many years is likely to increase. Close scrutiny on herb related safety and liver toxicities is strongly advocated. Toxic ingredients, reactive metabolites, organelle stress, bile salt export inhibition and immune response have been postulated in the pathogenesis of herb-induced liver injury (HILI). HILI is in analogy to drug induced liver injury (DILI) in following aspects (I) clinical manifestations: from asymptomatic abnormal liver tests to severe liver injury and liver failure requiring liver transplantation; (II) mechanism: idiosyncratic or intrinsic; and (III) phenotypes of injury: hepatocellular, cholestatic or mixed type. The diagnosis of HILI remains a challenge. Roussel Uclaf Causality Assessment Method (RUCAM), a structured, quantitative, effective and validated tool for HILI should be reinforced in clinical use. The pathogenetic hallmarks of genome-wide association study (GWAS), human leukocyte antigen (HLA) alleles and non-HLA genetic variants may determine the risk for HILI. Diagnostic biomarkers for HILI need to be re-investigated and reliably validated in future research for their clinical implications. Global prospective HILI registry with advances in the exploration of toxic ingredients, genetic testing and new biomarkers may better explain the pathogenesis and pathogenetic mechanism of HILI which can lead to improvement in diagnosis and treatment of DILI. Pharmacovigilance and standardized regulatory surveillance on safety and efficacy of herbs and herbal products are warranted to reduce the occurrence of HILI and its associated morbidity and mortality.

Drug Induced Liver Injury: Is there an Indication for Ursodeoxycholic Acid Use?

Drug induced liver injury (DILI) is one of the most conflicting diagnoses for hepatologists. DILI is defined as an acute or chronic liver injury, manifested by alteration of liver function tests, due to the consumption of medications, herbal or dietary supplements, after excluding other etiologies of liver disease. Several facts contribute to DILI; among them, host related factors, as age, sex, alcohol consumption and underlying chronic diseases; and drug related, as dose, lipophilicity, drug metabolism and interactions. Few treatments for DILI are actually recommended in current guidelines. Ursodeoxycholic acid (UDCA) use for DILI is debated, because of the lack of clinical trials proving its efficacy. Hence, in several case reports UDCA has been used for DILI with good results preventing the progression of the disease and the need of liver transplantation. Small series have also described the resolution or amelioration of DILI with the use of UDCA. Nonetheless, current guidelines do not support its wide use. The aim of this review is to discuss the current knowledge of DILI and the mechanisms of action and facts of the use of UDCA in DILI, making UDCA a promising alternative for the treatment of DILI. Keywords: Drug-induced liver injury, Ursodeoxycholic acid, biliary transporters, vanishing bile duct syndrome, cholestasis. Read more →

Bicyclol for the treatment of drug-induced liver injury: a propensity score matching analysis using a nationwide inpatient database.

ObjectiveTo evaluate the efficacy and safety of bicyclol in patients with drug-induced liver injury (DILI) using a nationwide database.MethodsWe retrospectively analyzed the clinical data of DILI patients in the DILI-R database. Propensity score matching was performed to balance the bicyclol and control groups, and alanine aminotransferase (ALT) recovery was compared between the two groups. Factors associated with ALT recovery and safety were identified.ResultsThe analysis included the data of 25,927 patients. Eighty-seven cases were included in the bicyclol group, with 932 cases in the control group. One-to-one propensity score matching created 86 matched pairs. The ALT normalization rate in the bicyclol group was significantly higher than that in the control group (50.00% vs. 24.42%), and statistical significance was found in the superiority test. After adjustment of baseline ALT levels, baseline total bilirubin levels, sex, age, acute or chronic liver diseases, and suspected drugs in the multivariate logic regression analysis, the major influencing factors for ALT recovery included the time interval between ALT tests (days) and the group factor (bicyclol treatment). There were no differences in the proportion of renal function impairment or blood abnormalities between the two groups.ConclusionsBicyclol is a potential candidate for DILI.

恶性血液病患者药物性肝损伤的预防和规范化治疗中国专家共识（2021年版）

恶性血液病患者药物性肝损伤的预防和规范化治疗中国专家共识（2021年版）

Elevated cAMP Protects against Diclofenac-Induced Toxicity in Primary Rat Hepatocytes: A Protective Effect Mediated by the Exchange Protein Directly Activated by cAMP/cAMP-Regulated Guanine Nucleotide Exchange Factors.

Chronic consumption of the nonsteroidal anti-inflammatory drug diclofenac may induce drug-induced liver injury (DILI). The mechanism of diclofenac-induced liver injury is partially elucidated and involves mitochondrial damage. Elevated cAMP protects hepatocytes against bile acid-induced injury. However, it is unknown whether cAMP protects against DILI and, if so, which downstream targets of cAMP are implicated in the protective mechanism, including the classic protein kinase A (PKA) pathway or alternative pathways like the exchange protein directly activated by cAMP (EPAC). The aim of this study was to investigate whether cAMP and/or its downstream targets protect against diclofenac-induced injury in hepatocytes. Rat hepatocytes were exposed to 400 µmol/l diclofenac. Apoptosis and necrosis were measured by caspase-3 activity assay and Sytox green staining, respectively. Mitochondrial membrane potential (MMP) was measured by JC-10 staining. mRNA and protein expression were assessed by quantitative polymerase chain reaction (qPCR) and Western blot, respectively. The cAMP-elevating agent 7β-acetoxy-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one (forskolin), the pan-phosphodiesterase inhibitor IBMX, and EPAC inhibitors 5,7-dibromo-6-fluoro-3,4-dihydro-2-methyl-1(2H)-quinoline carboxaldehyde (CE3F4) and ESI-O5 were used to assess the role of cAMP and its effectors, PKA or EPAC. Diclofenac exposure induced apoptotic cell death and loss of MMP in hepatocytes. Both forskolin and IBMX prevented diclofenac-induced apoptosis. EPAC inhibition but not PKA inhibition abolished the protective effect of forskolin and IBMX. Forskolin and IBMX preserved the MMP, whereas both EPAC inhibitors diminished this effect. Both EPAC1 and EPAC2 were expressed in hepatocytes and localized in mitochondria. cAMP elevation protects hepatocytes against diclofenac-induced cell death, a process primarily involving EPACs. The cAMP/EPAC pathway may be a novel target for treatment of DILI. SIGNIFICANCE STATEMENT: This study shows two main highlights. First, elevated cAMP levels protect against diclofenac-induced apoptosis in primary hepatocytes via maintenance of mitochondrial integrity. In addition, this study proposes the existence of mitochondrial cAMP-EPAC microdomains in rat hepatocytes, opening new avenues for targeted therapy in drug-induced liver injury (DILI). Both EPAC1 and EPAC2, but not protein kinase A, are responsible for this protective effect. Our findings present cAMP-EPAC as a potential target for the treatment of DILI and liver injury involving mitochondrial dysfunction.

A network pharmacology-integrated metabolomics strategy for clarifying the action mechanisms of Schisandrae Chinensis Fructus for treating drug-induced liver injury by acetaminophen

Schisandrae Chinensis Fructus (SCF) was a Traditional Chinese Medicine (TCM) for protecting liver. However, underlying therapeutic mechanisms of SCF for drug-induced liver injury (DILI) by acetaminophen (APAP) are still unclear. This study aims to discover the potential regulation mechanisms of SCF in the treatment of DILI by APAP using the integrated network pharmacology, plasma metabolomics profiling with UPLC-Q-TOF-MS approach. The key targets in the shared pathways of network pharmacology and metabolomics were screened and experimentally validated by Quantitative Real-time PCR analysis. The results showed that SCF could exert excellent effects on DILI by APAP probably through regulating ErbB signaling pathway and Arachidonic acid metabolism pathway, which was reflected by the reduced gene expression of TNF-α, IL-6, IL-1β, COX-2 and EGFR, as well as the increased gene expression of Nrf2, HO-1, MDM2, MAPK8, SRC, PLD1, CYP2E1, CYP1A2, CYP3A1. This study systematically explored the pharmacological mechanisms of SCF in the treatment of DILI, meanwhile, metabolomics combine with network pharmacology approach might be a useful strategy for early diagnosis of DILI by APAP.

Pathogenesis of drug-induced liver injury: Current understanding and future needs

The risk factors for drug-induced liver injury (DILI) involve host factors (including general non-genetic factors and idiosyncratic genetic and immune factors), drug-related factors, and environmental factors. The pathogenesis of DILI can be classified as intrinsic (or direct) hepatotoxicity, idiosyncratic hepatotoxicity, and indirect hepatotoxicity, as well as tumorigenicity and carcinogenicity of some drugs to the liver. The pathogenesis of different types of hepatotoxicity not only has significant differences, but also has internal correlation at multiple links. The three-step model centered on mitochondrial permeability transition (MPT) and a two-stage model with liver cell regeneration and liver tissue repair capacity as the determinants of different outcomes display the mechanism progress of DILI from different perspectives. Clarification of the complex pathogenesis of DILI needs long-term collection of clinical cases and systematic studies, which is of great significance for the scientific prevention, diagnosis, and treatment of DILI.

Drug-induced liver injury: Advances and confusions in treatment

Drug-induced liver injury (DILI) is one of the most common and serious adverse drug reactions and can lead to acute liver failure and even death in severe cases. The pathogenesis of DILI has not been fully clarified, and there is significant individual difference. There is no effective treatment for advanced DILI except liver transplantation, and therefore, early diagnosis and precise treatment are of particular importance. This article reviews the important research advances and difficult issues in the treatment of DILI in recent years.

CoQ10 protects against acetaminophen-induced liver injury by enhancing mitophagy

Coenzyme Q10 (CoQ10), which is a key cofactor of the electron transport chain in the mitochondria has shown many beneficial effects on liver diseases. However, the mechanisms of CoQ10 protective role on the acetaminophen (APAP)-induced liver injury are elusive and unclear. In this study, we further investigated the CoQ10 therapeutic effects on APAP-overdose liver injury. C57BL/6 J mice were intraperitoneally treated with APAP to induce liver injury. CoQ10 (5 mg/kg) was given to mice at 1.5 h after APAP treatment. The results showed that hepatic CoQ10 levels were decreased during the APAP-induced hepatotoxicity and preceded serum ALT elevation. Treatment of CoQ10 significantly improved the liver injury induced by APAP. Moreover, CoQ10 treatment decreased the ROS levels and promoted the antioxidative related gene expression in APAP overdose mice. Importantly, results showed that even though CoQ10 had no effects on the mtDNA copy number and the expression of genes related to mitochondrial biogenesis, it significantly improved the mitochondrial complex I and V activities and promoted the mitophagy in APAP-overdose mice. To further authenticate mitophagy role in CoQ10-mediated improved liver injury in vivo, we administrated APAP-overdose mice with chloroquine 1 h prior to APAP treatment and found that chloroquine treatment functionally abrogated the CoQ10 protective role on APAP overdose mice. To conclude, this study provides evidence that CoQ10 activates mitophagy to protect against APAP-induced liver injury. Therefore, CoQ10 may represent a novel therapeutic option for the prevention and treatment of drug-induced liver injury.

Drug-induced liver injury in cancer patients

This review includes information about epidemiological data, development feature, phenotypes, principles of classification, diagnosis, and prognosis for drug-induced liver injury (DILI). Actual clinical recommendations regarding management of the DILI arising in the chemotherapy of cancer discussed. Drugs that can influence on individual pathogenetic mechanisms of growth and symptoms DILI are considered. Clinical studies for the prophylaxis and treatment of DILI associated with anticancer chemotherapy analyzed in detail. The prevention and treatment regimens for DILI in patients receiving chemotherapy and immunotherapy various localizations of cancer given both in research and in practical recommendations.

Network Meta-analysis of traditional Chinese medicine in treating drug-induced liver injury

To systematically evaluate the efficacy and safety of Chinese medicine in the treatment of drug-induced liver injury(DILI). By searching the randomized controlled trials(RCTs) of the Chinese medicine published in CNKI, WanFang, VIP, PubMed, Web of Science, in a time limit from database establishment to May 1, 2020. The bias risk assessment and Meta-analysis were then conducted for the included studies. Seventeen studies were finally included, all of which were RCTs, including 1 407 patients. The experimental group was treated with Chinese herbal medicine decoction or Chinese patent medicine, involving a total of 11 kinds of drugs, and the control group was treated with conventional Western medicine. Meta-analysis results showed that, in terms of treatment effective rate, Yinlan Yigan Granules, Shuganning, Jiangmeiling Capsules, Baidan Shugan Recipe and Sini Shugan Decoction were all superior to Western medicine treatment. In terms of reducing alanine aminotransferase(ALT), Yinlan Yigan Granules, Shuganning, Hugan Jiedu Recipe, Wuzhi Tablets, Wucao Baogan Recipe and Liuwei Wuling Tablets were superior to Western medicine. In terms of reducing aspartate aminotransferase(AST), Shuganning, Hugan Jiedu Recipe, Wucao Baogan Recipe, Liuwei Wuling Tablets and Sini Shugan Decoction were all superior to Western medicine. In terms of reducing total bilirubin(TBiL), Yinlan Yigan Granules, Shuganning, Jiedu Hugan Yin, Wuzhi Tablets, Wucao Baogan Recipe, Baidan Shugan Recipe and Sini Shugan Decoction were all superior to Western medicine treatment. Combined with network Meta-analysis and probability ranking, it can be seen that, Jiangmeiling Capsules, Shuganning, Sini Shugan Decoction and Baidan Shugan Recipe were most likely to be the best drugs to improve the efficiency and reduce ALT, AST, TBiL, respectively, with certain advantages compared to conventional Western medicine treatment. Of the seventeen studies included, eight studies described safety issues, three of which involved the test group, all of which were minor adverse reactions that disappeared after drug withdrawal or symptomatic treatment. However, due to the low quality of the included studies, more high-quality clinical studies are needed for further verification, thus providing more evidence-based medical evidence for Chinese medicine intervention in DILI.

S‐allyl‐L‐cysteine protects hepatocytes from indomethacin‐induced apoptosis by attenuating endoplasmic reticulum stress

Drug-induced liver injury (DILI) can lead to acute liver failure, a lethal condition which may require liver transplantation. Hepatotoxicity associated with nonsteroidal anti-inflammatory drugs (NSAIDs) accounts for ~10% of all DILI. In the current study, we determined whether indomethacin, one of the most commonly used NSAIDS, induced apoptosis in hepatocytes and investigated the underlying mechanism. Meanwhile, we investigated the protective effect of S-allyl-L-cysteine (SAC), an active garlic derivative, on indomethacin-induced hepatocyte apoptosis, and its implication on endoplasmic reticulum (ER) stress. We found that indomethacin triggered ER stress, as indicated by the elevated expression of phosphorylated eukaryotic translation initiation factor 2α (eIF2α), C/EBP homologous protein (CHOP) and spliced XBP1 in a rat liver BRL-3A cell line. Following indomethacin treatment, caspase 3 activation and hepatocyte apoptosis were also observed. Inhibition of ER stress by chemical chaperone 4-phenyl butyric acid alleviated cell apoptosis caused by indomethacin, indicating that ER stress is involved in indomethacin-induced hepatocyte apoptosis. Moreover, SAC abated indomethacin-induced eIF2α phosphorylation, inhibited CHOP upregulation and its nuclear translocation, abrogated the activation of caspase 3 and finally, protected hepatocytes from apoptosis. In conclusion, SAC protects indomethacin-induced hepatocyte apoptosis through mitigating ER stress and may be suitable for development into a potential new therapeutic agent for the treatment of DILI.

Drug-induced liver injury and liver injury during pregnancy: pathogenesis, diagnosis and treatment

This article is a literature review on drug-induced liver injury (DILI). The authors revealed the role of liver tissue in biotransformation of drugs, and the mechanisms of hepatocytes injury under the influence of their metabolites (direct lesion of hepatocytes structure and idiosyncratic hypersensitivity). Separation of drugs into true and facultative hepatotoxins is explained. Opinion of patients and doctors of various majors about the most hepatotoxic drugs is presented. DILI classification depending on the dominant pathogenetic mechanism is given. Nuances of clinical and laboratory diagnostics and drug treatment of DILI are revealed. Advantages of ademetionine, ursodeoxycholic acid and glucocorticoids prescription are analyzed, indications for their application are listed, and the optimal therapeutic dosages of these drugs are given. Expediency of prescribing plant hepatoprotector chophytol and myotropic spasmolytic hymecromone is considered.&#x0D; Pathogenesis of liver injury during pregnancy is described, occurrence of hepatological pathology in this cohort of patients is briefly characterized, nuances of diagnostics and course of intrahepatic cholestasis of pregnancy, acute fatty liver dystrophy of pregnancy, HELLP-syndrome are considered. Peculiarities of the course of pregnancy on the background of the previous liver disease (viral hepatitis A, B, C, autoimmune hepatitis, primary biliary cirrhosis, Wilson’s disease) are revealed. The most effective conservative (ademetionine, ursodeoxycholic acid) and operative techniques (early delivery) of correction of liver injury of pregnancy are listed.

Systematic Elucidation of the Potential Mechanism of Erzhi Pill against Drug-Induced Liver Injury via Network Pharmacology Approach.

Objective The purpose of this work was to investigate the bioactive compounds, core genes, and pharmacological mechanisms and to provide a further research orientation of Erzhi pill (EZP) on drug-induced liver injury (DILI). Methods At first, we collected information of bioactive compounds of EZP from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and previous studies. And then, the targets related to bioactive compounds and DILI were obtained from 4 public databases. At last, Cytoscape was used to establish a visual network. Moreover, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses and network analysis were performed to investigate potential mechanism of EZP against DILI. Results A total of 23 bioactive compounds and 89 major proteins of EZP were screened out as potential players against DILI. Association for bioactive compounds, core targets, and related pathways was analyzed, implying that core targets related to these pathways are ALB, AKT1, MAPK1, EGFR, SRC, MAPK8, IGF1, CASP3, HSP90AA1, and MMP9, and potential mechanisms of EZP acting on DILI are closely related to negative regulation of apoptosis process, improvement of lipid metabolism, and positive regulation of liver regeneration process. Conclusion This study demonstrated the multicompound, multitarget, and multichannel characteristics of EZP, which provided a novel approach for further research the mechanism of EZP in the treatment of DILI.

Visualization of Dynamic Changes in Labile Iron(II) Pools in Endoplasmic Reticulum Stress-Mediated Drug-Induced Liver Injury.

Drug-induced liver injury (DILI) can cause liver failure and even death in severe cases, gravely threatening human health. The treatment of DILI remains a clinical challenge, mainly due to the lack of efficient and accurate diagnosis. Therefore, developing an accurate diagnosis approach is imperative to boost the timely treatment for DILI. As the primary organ of iron storage, liver's functions are tightly linked to iron homeostasis. Thus, monitoring iron homeostasis is promising for the diagnosis and treatment of DILI. Hence, we reported a new near-infrared fluorescent probe (LCy7) that enables real-time and in vivo visualizing of Fe2+ in drug-induced liver injury. In this design, Fe2+ would bind to the N4O ligand in LCy7 and conduce to the C-O bond broken in the presence of O2, which restore the masked QCy7 emitting luminous near-infrared fluorescence. Utilizing LCy7, the increase in Fe2+ was distinctly witnessed in hepatocytes under endoplasmic reticulum stress by acetaminophen (APAP) stimulation. In vivo near-infrared fluorescence imaging revealed the conspicuous rise in Fe2+ in the liver of mice during APAP-induced liver injury. We further unprecedentedly disclosed that endoplasmic reticulum stress was accompanied by the overload of Fe2+ in injured liver of these mice. Collectively, this work will facilitate a greater understanding of the pathogenesis of DILI, and also provide a powerful new tool for DILI diagnosis and treatment.

CCL5 deficiency promotes liver repair by improving inflammation resolution and liver regeneration through M2 macrophage polarization.

Despite the diverse etiologies of drug-induced liver injury (DILI), innate immunity activation is a common feature involved in DILI progression. However, the involvement of innate immunity regulation in inflammation resolution and liver regeneration in DILI remains obscure. Herein, we identified the chemokine CCL5 as a central mediator of innate immunity regulation in the pathogenesis of DILI. First, we showed that serum and hepatic CCL5 levels are elevated in both DILI patients and an APAP-induced liver injury (AILI) mouse model. Interestingly, both nonparenchymal cells and stressed hepatocytes are cell sources of CCL5 induction in response to liver injury. Functional experiments showed that CCL5 deficiency has no effect on the early phase of AILI but promotes liver repair in the late phase mainly by promoting inflammation resolution and liver regeneration, which are associated with an increased number of hepatic M2 macrophages. Mechanistically, CCL5 can directly activate M1 polarization and impede M2 polarization through the CCR1- and CCR5-mediated activation of the MAPK and NF-κB pathways. We then showed that CCL5 inhibition mediated by either a CCL5-neutralizing antibody or the antagonist Met-CCL5 can greatly alleviate liver injury and improve survival in an AILI mouse model. Our data demonstrate CCL5 induction during DILI, identify CCL5 as a novel innate immunity regulator in macrophage polarization, and suggest that CCL5 blockage is a promising therapeutic strategy for the treatment of DILI.

Drug-induced liver injury.

Drug-induced liver injury (DILI), including herbal and dietary supplement hepatotoxicity, is often passed lightly; however, it can lead to the requirement of a liver transplant or may even cause death because of liver failure. Recently, the American College of Gastroenterology, Chinese Society of Hepatology and European Association for the Study of the Liver guidelines for the diagnosis and treatment of DILI have been established, and they will be helpful for guiding clinical treatment decisions. Roussel Uclaf Causality Assessment Method scoring is the most commonly used method to diagnose DILI; however, it has some limitations, such as poor validity and reproducibility. Recently, studies on new biomarkers have been actively carried out, which will help diagnose DILI and predict the prognosis of DILI. It is expected that the development of new therapies such as autophagy inducers and various other technologies of the fourth industrial revolution will be applicable to DILI research.