Tetrahydroxy stilbene glucoside rejuvenates aging hematopoietic stem cells with predilection for lymphoid differentiation via AMPK and Tet2.

INTRODUCTION: Aging of hematopoietic stem cells (HSCs) has emerged as an important challenge to human health. Recent advances have raised the prospect of rejuvenating aging HSCs via specific medical interventions, including pharmacological treatments. Nonetheless, efforts to develop such drugs are still in infancy until now. OBJECTIVES: We aimed to screen the prospective agents that can rejuvenate aging HSCs and explore the potential mechanisms. METHODS: We screened a set of natural anti-aging compounds through oral administration to sub-lethally irradiated mice, and identified 2,3,5,4'-tetrahydroxystilbene-2-O-ß-D-glucoside (TSG) as a potent rejuvenating agent for aging HSCs. Then naturally aged mice were used for the follow-up assessment to determine the HSC rejuvenating potential of TSG. Finally, based on the transcriptome and DNA methylation analysis, we validated the role of the AMP-activated protein kinase (AMPK)-ten-eleven-translocation 2 (Tet2) axis (the AMPK-Tet2 axis) as the underlying mechanisms of TSG for ameliorating HSCs aging. RESULTS: TSG treatment not only significantly increased the absolute number of common lymphoid progenitors (CLPs) along with B lymphocytes, but also boosted the HSCs/CLPs repopulation potential of aging mice. Further elaborated mechanism research demonstrated that TSG supplementation restored the stemness of aging HSCs, as well as promoted an epigenetic reprograming that was associated with an improved regenerative capacity and an increased rate of lymphopoiesis. Such effects were diminished when the mice were co-treated with an AMPK inhibitor, or when it was performed in Tet2 knockout mice as well as senescent cells assay. CONCLUSION: TSG is effective in rejuvenating aging HSCs by modulating the AMPK- Tet2 axis and thus represents a potential candidate for developing effective HSC rejuvenating therapies.

Bibliometric and visualized analysis of hydrogels in organoids research.

Over the past decades, there has been ongoing effort to develop complex biomimetic tissue engineering strategies for in vitro cultivation and maintenance of organoids. The defined hydrogels can create organoid models for various organs by changing their properties and various active molecules. An increasing number of researches has been done on the application of hydrogels in organoids, and a large number of articles have been published on the topic. Although there have been existing reviews describing the application of hydrogels in the field of organoids, there is still a lack of comprehensive studies summarizing and analyzing the overall research trends in this field. The citation can be used as an indicator of the scientific influence of an article in its field. This study aims to evaluate the application of hydrogels in organoids through bibliometric analysis, and to predict the hotspots and developing trends in this field.

No Incidence of Liver Cancer Was Observed in A Retrospective Study of Patients with Aristolochic Acid Nephropathy.

OBJECTIVE: To assess the risk of aristolochic acid (AA)-associated cancer in patients with AA nephropathy (AAN). METHODS: A retrospective study was conducted on patients diagnosed with AAN at Peking University First Hospital from January 1997 to December 2014. Long-term surveillance and follow-up data were analyzed to investigate the influence of different factors on the prevalence of cancer. The primary endpoint was the incidence of liver cancer, and the secondary endpoint was the incidence of urinary cancer during 1 year after taking AA-containing medication to 2014. RESULTS: A total of 337 patients diagnosed with AAN were included in this study. From the initiation of taking AA to the termination of follow-up, 39 patients were diagnosed with cancer. No cases of liver cancer were observed throughout the entire follow-up period, with urinary cancer being the predominant type (34/39, 87.17%). Logistic regression analysis showed that age, follow-up period, and diabetes were potential risk factors, however, the dosage of the drug was not significantly associated with urinary cancer. CONCLUSIONS: No cases of liver cancer were observed at the end of follow-up. However, a high prevalence of urinary cancer was observed in AAN patients. Establishing a direct causality between AA and HCC is challenging.

[Interpretation on Consensus on drug-induced liver injury by CIOMS Working Group:liver injury attributed to herbal and dietary supplements].

With the increase in the medical level, the improvement of adverse drug reaction(ADR) monitoring systems, and the enhancement of public awareness of safe medication, drug safety incidents have been frequently reported. Drug-induced liver injury(DILI), especially liver injury attributed to herbal and dietary supplements(HDS), has globally attracted high attention, bringing great threats and severe challenges to the people for drug safety management such as clinical medication and medical supervision. Consensus on drug-induced liver injury had been published by the Council for International Organizations of Medical Sciences(CIOMS) in 2020. In this consensus, liver injury attributed to HDS was included in a special chapter for the first time. The hot topics, including the definition of HDS-induced liver injury, epidemiological history, potential risk factors, collection of related risk signals, causality assessment, risk prevention, control and management were discussed from a global perspective. Based on the previous works, some experts from China were invited by CIOMS to undertake the compilation of this chapter. Meanwhile, a new causality assessment in DILI based on the integrated evidence chain(iEC) method was widely recognized by experts in China and abroad, and was recommended by this consensus. This paper briefly introduced the main contents, background, and characteristics of the Consensus on drug-induced liver injury. Significantly, a brief interpretation was illustrated to analyze the special highlights of Chapter 8, "Liver injury attributed to HDS", so as to provide practical references for the medical staff and the researchers who worked on either Chinese or Western medicine in China.

[New outlook on safety of traditional Chinese medicine: concept and practice].

Profound changes have taken place in human disease spectrum, constitution spectrum, and drug use behavior, and the safety of traditional Chinese medicine(TCM) faces new trends and problems. In particular, serious adverse reactions/events such as liver injury and kidney injury caused by non-toxic TCM have been frequently reported, overturning people's understanding of TCM safety, and even shaking the public's confidence in the development of TCM. In the new era of globalization, correctly understanding the situation and problems of TCM safety and addressing the dilemmas in safety evaluation and risk prevention of TCM are the key missions to be undertaken by TCM practitioners. This paper suggests that the situation and problems of TCM safety should be viewed objectively and dialectically, and the use standard of TCM should be advanced with the times. Furthermore, this paper puts forward the new conception and methodology of TCM safety(including one innovative understanding, two types of evaluation modes, tri-elements injury hypothesis; four-quadrant risk decision processes, and five-grade safety evidence body) for the first time, hoping to provide new theories, new strategies, new methods and successful examples for solving the safety problems of TCM.

A clinical experience-based Chinese herbal formula improves ethanol-induced drunken behavior and hepatic steatohepatitis in mice models.

BACKGROUND: Bao-Gan-Xing-Jiu-Wan (BGXJW) is a clinical experience-based Chinese herbal formula. Its efficacy, pharmacological safety, targeted function, process quality, and other aspects have met the evaluation standards and the latest requirements of preparations. It could prevent and alleviate the symptoms of drunkenness and alcoholic liver injury clinically. The present work aims to elucidate whether BGXJW could protect against drunkenness and alcoholic liver disease in mice and explore the associated mechanism. MATERIAL AND METHODS: We used acute-on-chronic (NIAAA) mice model to induce alcoholic steatosis, and alcohol binge-drinking model to reappear the drunk condition. BGXJW at indicated doses were administered by oral gavage respectively to analyze its effects on alcoholic liver injury and the associated molecular mechanisms. RESULTS: BGXJW had no cardiac, hepatic, renal, or intestinal toxicity in mice. Alcoholic liver injury and steatosis in the NIAAA mode were effectively prevented by BGXJW treatment. BGXJW increased the expression of alcohol metabolizing enzymes ADH, CYP2E1, and ALDH2 to enhance alcohol metabolism, inhibited steatosis through regulating lipid metabolism, counteracted alcohol-induced upregulation of lipid synthesis related proteins SREBP1, FASN, and SCD1, meanwhile it enhanced fatty acids ß-oxidation related proteins PPAR-α and CPT1A. Alcohol taken enhanced pro-inflammatory TNF-α, IL-6 and down-regulated the anti-inflammatory IL-10 expression in the liver, which were also reversed by BGXJW administration. Moreover, BGXJW significantly decreased the blood ethanol concentration and alleviated drunkenness in the alcohol binge-drinking mice model. CONCLUSIONS: BGXJW could effectively relieve drunkenness and prevent alcoholic liver disease by regulating lipid metabolism, inflammatory response, and alcohol metabolism.

New Insights into Herb-Induced Liver Injury.

Significance: Herbs are widely used worldwide. However, inappropriate use of some of the herbs can lead to herb-induced liver injury (HILI). Intriguingly, HILI incidents are on the rise, and our understanding of the underlying etiologies is in progress, and hence, an update on the current status of incidents as well as our understanding on the etiologies of HILI is appropriate. Recent Advances: HILI reports due to the use of some herbs that are traditionally considered to be safe are also on the rise. Furthermore, HILI due to the use of certain herbs in combination with other herbs (herb-herb interaction [HHI]) or non-herb components (herb-drug interaction [HDI]) has also been reported, suggesting a potentially important new type of inappropriate use of herbs. Critical Issues: Updated overviews focus on the epidemiology, etiology, phenotypes, and risk factors of HILI, as well as HDI and HHI, and analysis on several types of newly reported "toxic" effects of herbs based on types of hepatotoxicity and the HILI mechanisms. Future Directions: HILI will continue to be a significant public health challenge in the near future. In the light of the lack of broadly available guidelines and regulations for proper and safe uses of herbs worldwide, raising the public awareness of HILI will remain one of the most effective measures. In particular, it should include a better understanding of the contributing factors; a more detail subclassification and description of HILI, better characterization of the components/substances that could induce HILI; and development of HILI diagnosis based on the Roussel Uclaf Causality Assessment Method (RUCAM). Antioxid. Redox Signal. 38, 1138-1149.

Correction: Clinical correlation between serum cytokines and the susceptibility to Polygonum multiflorum-induced liver injury and an experimental study.

Correction for 'Clinical correlation between serum cytokines and the susceptibility to Polygonum multiflorum-induced liver injury and an experimental study' by Le Zhang et al., Food Funct., 2022, 13, 825-833, https://doi.org/10.1039/D1FO03489H.

Best Practice in the chemical characterisation of extracts used in pharmacological and toxicological research-The ConPhyMP-Guidelines.

Background: Research on medicinal plants and extracts derived from them differs from studies performed with single compounds. Extracts obtained from plants, algae, fungi, lichens or animals pose some unique challenges: they are multicomponent mixtures of active, partially active and inactive substances, and the activity is often not exerted on a single target. Their composition varies depending on the method of preparation and the plant materials used. This complexity and variability impact the reproducibility and interpretation of pharmacological, toxicological and clinical research. Objectives: This project develops best practice guidelines to ensure reproducibility and accurate interpretations of studies using medicinal plant extracts. The focus is on herbal extracts used in pharmacological, toxicological, and clinical/intervention research. Specifically, the consensus-based statement focuses on defining requirements for: 1) Describing the plant material/herbal substances, herbal extracts and herbal medicinal products used in these studies, and 2) Conducting and reporting the phytochemical analysis of the plant extracts used in these studies in a reproducible and transparent way. The process and methods: We developed the guidelines through the following process: 1) The distinction between the three main types of extracts (extract types A, B, and C), initially conceptualised by the lead author (MH), led the development of the project as such; 2) A survey among researchers of medicinal plants to gather global perspectives, opportunities, and overarching challenges faced in characterising medicinal plant extracts under different laboratory infrastructures. The survey responses were central to developing the guidelines and were reviewed by the core group; 3) A core group of 9 experts met monthly to develop the guidelines through a Delphi process; and. 4) The final draft guidelines, endorsed by the core group, were also distributed for feedback and approval to an extended advisory group of 20 experts, including many journal editors. Outcome: The primary outcome is the "Consensus statement on the Phytochemical Characterisation of Medicinal Plant extracts" (ConPhyMP) which defines the best practice for reporting the starting plant materials and the chemical methods recommended for defining the chemical compositions of the plant extracts used in such studies. The checklist is intended to be an orientation for authors in medicinal plant research as well as peer reviewers and editors assessing such research for publication.

Tetrahydroxy stilbene glucoside alters neurogenesis and neuroinflammation to ameliorate radiation-associated cognitive disability via AMPK/Tet2.

Along with the extensive application of radiation in medical, military and other fields, human beings carry a greater risk of exposure to radiation environment that causes a range of physical injure, particularly to the brain in cognition. However, the radiation-associated cognitive disability is poorly understood and there is no effective prevention or long-term treatment. Here, we demonstrate that neurogenesis and neuroinflammation disorder are primarily involved in the pathophysiological basis of irradiation-induced cognitive decline. Furthermore, we discovered that tetrahydroxy stilbene glucoside (TSG), a natural active ingredient from Heshouwu that has been well known for its unique anti-aging effect as the Chinese herb, can be a promising mitigator to improve learning-memory ability by facilitating the neurogenesis in the proliferation and differentiation of the surviving neural progenitor cells via AMPK/Tet2, and attenuating the neuroinflammation in the microglial NLRP3 inflammasomes activation via AMPK in vivo. Additionally, TSG was also revealed to activate AMPK by molecular docking and kinase enzyme system assay in vitro. Taken together, our findings identify TSG, as the AMPK activator, prevents radiation-induced cognitive dysfunction by regulating neurogenesis and neuroinflammation via AMPK/Tet2 in rodents, and represents a very promising candidate for developing drugs that can be used for radiation-associated brain injury.

Metabolomic profiling for drug-induced liver injury with autoantibodies.

BACKGROUNDS: Drug induced liver injury (DILI) is sometimes similar to autoimmune hepatitis (AIH) in serology and histology. Clinicians empirically screened DILI with significant autoimmune characteristics to implement clinical intervention. We tried to characterize DILI with autoantibodies by metabolomics. METHODS: Untargeted metabolomics coupled with pattern recognition approaches were performed on sera samples including AIH (n = 59), DILI with autoantibodies (DILIAb+, n = 68), and DILI without autoantibodies (DILIAb-, n = 75). The differential metabolites and fingerprint metabolites between AIH and DILIAb- were screened by orthogonal partial least squares-discriminant analysis and hierarchical clustering respectively. RESULTS: Of the 388 annotated differential metabolites between AIH and DILIAb-, 74 fingerprint metabolites were screened. The eigenmetabolite compressed from the fingerprint possessed high discrimination efficacy (AUC:0.891; 95 %CI, 0.838-0.944). In the fingerprint-based PCA model, AIH and DILIAb- were separated into three regions: the "pure region" of AIH (Region 1), the "pure region" of DILIAb- (Region 3), the mixture region of AIH and DILIAb- (Region 2). After incorporated into the PCA model, DILIAb+ samples were distributed into the three regions, indicating that DILIAb+ samples had different etiological tendencies. Moreover, the fingerprint-based radar model verified the results of PCA model characterizing DILIAb+. Notably, the antibody titers of DILIAb+ in the three regions did not differ significantly, while the response rates for glucocorticoids were obviously different. The metabolic difference among DILIAb+ in different regions mainly lies in energy metabolism. CONCLUSIONS: In terms of metabolic signature, DILIAb+ may not be a community of same pathogenesis, including AIH-inclined parts. Which deserves further study.

Entecavir plus Biejia-Ruangan compound reduces the risk of hepatocellular carcinoma in Chinese patients with chronic hepatitis B.

BACKGROUND & AIMS: Chronic hepatitis B (CHB) and liver fibrosis are associated with a high risk of hepatocellular carcinoma (HCC) development. We assessed whether entecavir (ETV) plus Biejia-Ruangan compound (BRC), an anti-fibrotic traditional Chinese medicine, can further reduce the risk of HCC in treatment-naïve Chinese patients with CHB and an Ishak fibrosis score of ≥3 points derived from our parent double-blind randomized placebo-controlled trial. METHODS: After a 72-week comparison between ETV+BRC and ETV+placebo treatment, participants were eligible to enter an open-label treatment phase and were followed up every 6 months. The primary [secondary] endpoints were the incidence of HCC [liver-related deaths, non-HCC events, and non-liver-related deaths]. Modified intention-to-treat (mITT), intention-to-treat (ITT), and per-protocol (PP) populations were defined for the time-to-event analysis. RESULTS: A total of 1,000 patients were recruited; the median age was 42.0 years; 69.9% were male and 58.3% were HBeAg positive. In the mITT population, the 7-year cumulative incidence of HCC [liver-related deaths] was 4.7% [0.2%] for ETV+BRC, which was significantly lower than 9.3% [2.2%] for ETV monotherapy (p = 0.008 [p = 0.030]). Notably, ETV+BRC treatment yielded a lower incidence of HCC in those who did not achieve regression of fibrosis at week 72 than ETV monotherapy (p = 0.018). There were no differences in the other 2 secondary endpoints or safety profiles between the groups. Multivariable Cox proportional regression analysis, including the treatment allocation as a parameter, also demonstrated that ETV+BRC treatment was associated with a reduced incidence of HCC. The ITT and PP analyses showed consistent results. CONCLUSIONS: ETV plus BRC combination treatment could further reduce the risk of HCC and liver-related deaths in patients with CHB and advanced fibrosis or cirrhosis, which may have important clinical implications for HCC prevention. LAY SUMMARY: Patients with chronic hepatitis B virus infection are at an increased risk of developing liver cancer (specifically hepatocellular carcinoma [HCC]). While there are effective antiviral treatments that can suppress the virus in chronically infected patients, the risk of HCC remains. Herein, we show that adding a traditional Chinese medicine called Biejia-Ruangan compound to an antiviral reduced the risk of HCC in patients with chronic hepatitis B.

[Cognition innovation of toxicity of Chinese medicine and safe and precise medication].

Traditional Chinese medicine(TCM) has made outstanding contributions to disease prevention and treatment, survival, and reproduction of the Chinese nation. Currently, the inheritance and innovative development of TCM have become a national strategy. However, in recent years, adverse reactions/events of Chinese medicine frequently occurred. In particular, in terms of the safety problem of newly discovered "toxic" Chinese medicine, it is often difficult to answer the question scientifically and develop effective solutions. When facing international public opinions and public questioning, they are often "passively criticized". To solve the difficult problem about the safety of Chinese medicine, we urgently need to make breakthroughs in the cognition of toxicity of Chinese medicine and prevention and control of risks. This research team has been committed to the research on the safety of Chinese medicine for the long term. In particular, in terms of safety evaluation and risk prevention and control of newly discovered "toxic" Chinese medicine, they have made a series of original discoveries. On the basis of the discoveries, they innovated the cognition theory and methods of the toxicity of Chinese medicine, opened up a new field of research on the idiosyncratic toxicity and indirect toxicity of Chinese medicine, and proposed and established the disease-syndrome-based toxicology(DSBT), the model and method of safety evaluation of Chinese medicine related to diseases and syndromes. In light of the theory and methods of DSBT which have been applied to the objective eva-luation and analysis of the mechanism of the hepatotoxicity of Chinese medicine such as Polygoni Multiflori Radix, the mechanism hypothesis of "toxicity due to three causes" of idiosyncratic hepatotoxicity of Chinese medicine was proposed and confirmed. The findings revealed that the substances that induced idiosyncratic or indirect toxicity in Chinese medicine often did not possess definite direct toxi-city. Therefore, this research team proposed the concept of toxicity-related substances(TRS) in Chinese medicine. Based on the mo-dern scientific cognition of toxicity of Chinese medicine, the team proposed the strategy and method of Chinese medicine compatibility to reduce the toxicity based on the component-effect-target interaction to underpin the demonstration of the scientific connotation of toxicity and side effects of "toxic" Chinese medicine and establishment of scientific and effective risk prevention and control strategies. In light of the innovative development of toxicity cognition of Chinese medicine, this study is expected to provide important theoretical guidance and methodological support for scientific evaluation and precise prevention and control of the safety risk of "toxic" Chinese medicine.

Hepatic Organoid-Based High-Content Imaging Boosts Evaluation of Stereoisomerism-Dependent Hepatotoxicity of Stilbenes in Herbal Medicines.

The complexity of chemical components of herbal medicines often causes great barriers to toxicity research. In our previous study, we have found the critical divergent hepatotoxic potential of a pair of stilbene isomers in a famous traditional Chinese herb, Polygonum multiflorum (Heshouwu in Chinese). However, the high-throughput in vitro evaluation for such stereoisomerism-dependent hepatotoxicity is a critical challenge. In this study, we used a hepatic organoids-based in vitro hepatotoxic evaluation system in conjunction with using high content imaging to differentiate in vivo organ hepatotoxicity of the 2,3,5,4'-tetrahydroxy-trans-stilbene-2-O-ß-glucoside (trans-SG) and its cis-isomer (cis-SG). By using such an organoid platform, we successfully differentiated the two stereoisomers' hepatotoxic potentials, which were in accordance with their differences in rodents and humans. The lesion mechanism of the toxic isomer (cis-SG) was further found as the mitochondrial injury by high-content imaging, and its hepatotoxicity could be dose-dependently inhibited by the mitochondrial protective agent. These results demonstrated the utility of the organoids-based high-content imaging approach in evaluating and predicting organ toxicity of natural products in a low-cost and high-throughput way. It also suggested the rationale to use long-term cultured organoids as an alternative toxicology platform to identify early and cautiously the hepatotoxic new drug candidates in the preclinical phase.

Metabolomic Analysis Uncovers Lipid and Amino Acid Metabolism Disturbance During the Development of Ascites in Alcoholic Liver Disease.

Ascites is one of the most common complications of cirrhosis, and there is a dearth of knowledge about ascites-related pathologic metabolism. In this study, 122 alcoholic liver disease (ALD) patients, including 49 cases without ascites, 18 cases with mild-ascites, and 55 cases with large-ascites (1) were established according to the International Ascites Club (2), and untargeted metabolomics coupled with pattern recognition approaches were performed to profile and extract metabolite signatures. A total of 553 metabolites were uniquely discovered in patients with ascites, of which 136 metabolites had been annotated in the human metabolome database. Principal component analysis (PCA) analysis was used to further identify 21 ascites-related fingerprints. The eigenmetabolite calculated by reducing the dimensions of the 21 metabolites could be used to effectively identify those ALD patients with or without ascites. The eigenmetabolite showed a decreasing trend during ascites production and accumulation and was negatively related to the disease progress. These metabolic fingerprints mainly belong to the metabolites in lipid metabolism and the amino acid pathway. The results imply that lipid and amino acid metabolism disturbance may play a critical role in the development of ascites in ALD patients and could be a potent prognosis marker.

Metabolomic Profiling for Histologically Fibrotic Stage in Chronic Drug-Induced Liver Injury.

Background and aims: Chronic drug-induced liver injury (DILI) is a rare but under-researched adverse drug reaction-related disease, which is highly likely to progress into liver fibrosis and even cirrhosis. In this study, metabolomics was used to screen out characteristic metabolites related to the histological progression of fibrosis in chronic DILI and analyze the metabolic changes during the development of fibrosis to explain the underlying mechanism. Methods: Chronic DILI patients who underwent liver biopsy were divided into different fibrosis grades. Serum was analyzed by untargeted metabolomics to find serological characteristic metabolite fingerprints. The screened fingerprints were validated by the validation group patients, and the identification ability of fingerprints was compared using FibroScan. Results: A total of 31 metabolites associated with fibrosis and 11 metabolites associated with advanced fibrosis were identified. The validation group confirmed the accuracy of the two metabolite fingerprints [area under the curve (AUC) value 0.753 and 0.944]. In addition, the fingerprints showed the ability to distinguish the grades of fibrosis by comparing using FibroScan. The metabolite fingerprint pathway showed that bile acid synthesis is disturbed while lipid metabolism is extremely active, resulting in an overload of lipid metabolites in the occurrence and development of chronic DILI-associated fibrosis. Conclusions: Our metabolomic analysis reveals the unique metabolomic fingerprints associated with chronic DILI fibrosis, which have potential clinical diagnostic and prognostic significances. The metabolomic fingerprints suggest the disturbance of the lipid metabolites as the most important factor in the development of DILI fibrosis.

Corticosteroid plus glycyrrhizin therapy for chronic drug- or herb-induced liver injury achieves biochemical and histological improvements: a randomised open-label trial.

BACKGROUND: Treatment of chronic drug-induced liver injury (DILI) or herb-induced liver injury(HILI) is an important and unresolved challenge. There is no consensus regarding the indications for corticosteroids for chronic DILI/HILI. AIMS: To investigate the efficacy and safety of corticosteroid plus glycyrrhizin for patients with chronic DILI/HILI. METHODS: This was a randomised open-label trial. Eligible patients with causality assessment using the updated RUCAM were randomly assigned (1:1) either to the steroid treatment group (48-week stepwise dose reduction of methylprednisolone plus glycyrrhizin) or control group (glycyrrhizin alone). Liver biopsies were performed at baseline and at the end of the 48-week treatment period. The primary outcome was the proportion of patients with sustained biochemical response (SBR). The secondary outcomes were improvement in liver histology, time to biochemical normalisation and safety. RESULTS: Of 80 participants, 70 (87.5%) completed the trial. The patients were predominantly female (77.5%), aged >40 years (77.5%) and had a hepatocellular injury pattern of DILI (71.2%). Compared to the control group, the treatment group showed a higher proportion of SBR (94.3% vs. 71.4%, p = 0.023), shorter biochemical normalisation time and histological improvements in both histological activity and fibrosis. The DILI and HILI subgroups, as well as the autoimmune hepatitis (AIH)-like DILI and non-AIH-like subgroups, showed comparable responses. No severe adverse events were observed during the trial. CONCLUSION: This study provides the first clinical evidence that corticosteroid plus glycyrrhizin therapy for chronic DILI with or without AIH-like features can achieve both biochemical response and histological improvements with good safety. (ClinicalTrials.gov, NCT02651350).