Hongqin Xu

•ALDH2 deficiency is associated with an increased risk of HCC from cirrhosis in those who drink alcohol. •Chronic CCl4+EtOH treatment induces greater hepatic mitochondrial DNA damage in Aldh2-deficient mice than WT mice. •Oxidized mitochondrial DNA is delivered to HCC cells via hepatocyte-derived extracellular vesicles. •Oxidized mitochondrial DNA and acetaldehyde synergistically promote ROS production and multiple oncogenic pathways. Background & Aims Excessive alcohol consumption is one of the major causes of hepatocellular carcinoma (HCC). Approximately 30–40% of the Asian population are deficient for aldehyde dehydrogenase 2 (ALDH2), a key enzyme that detoxifies the ethanol metabolite acetaldehyde. However, how ALDH2 deficiency affects alcohol-related HCC remains unclear. Methods ALDH2 polymorphisms were studied in 646 patients with viral hepatitis B (HBV) infection, who did or did not drink alcohol. A new model of HCC induced by chronic carbon tetrachloride (CCl4) and alcohol administration was developed and studied in 3 lines of Aldh2-deficient mice: including Aldh2 global knockout (KO) mice, Aldh2*1/*2 knock-in mutant mice, and liver-specific Aldh2 KO mice. Results We demonstrated that ALDH2 deficiency was not associated with liver disease progression but was associated with an increased risk of HCC development in cirrhotic patients with HBV who consumed excessive alcohol. The mechanisms underlying HCC development associated with cirrhosis and alcohol consumption were studied in Aldh2-deficient mice. We found that all 3 lines of Aldh2-deficient mice were more susceptible to CCl4 plus alcohol-associated liver fibrosis and HCC development. Furthermore, our results from in vivo and in vitro mechanistic studies revealed that after CCl4 plus ethanol exposure, Aldh2-deficient hepatocytes produced a large amount of harmful oxidized mitochondrial DNA via extracellular vesicles, which were then transferred into neighboring HCC cells and together with acetaldehyde activated multiple oncogenic pathways (JNK, STAT3, BCL-2, and TAZ), thereby promoting HCC. Conclusions ALDH2 deficiency is associated with an increased risk of alcohol-related HCC development from fibrosis in patients and in mice. Mechanistic studies reveal a novel mechanism that Aldh2-deficient hepatocytes promote alcohol-associated HCC by transferring harmful oxidized mitochondrial DNA-enriched extracellular vesicles into HCC and subsequently activating multiple oncogenic pathways in HCC. Lay summary Alcoholics with an ALDH2 polymorphism have an increased risk of digestive tract cancer development, however, the link between ALDH2 deficiency and hepatocellular carcinoma (HCC) development has not been well established. In this study, we show that ALDH2 deficiency exacerbates alcohol-associated HCC development both in patients and mouse models. Mechanistic studies revealed that after chronic alcohol exposure, Aldh2-deficient hepatocytes produce a large amount of harmful oxidized mitochondrial DNA via extracellular vesicles, which can be delivered into neighboring HCC cells and subsequently activate multiple oncogenic pathways, promoting HCC. Excessive alcohol consumption is one of the major causes of hepatocellular carcinoma (HCC). Approximately 30–40% of the Asian population are deficient for aldehyde dehydrogenase 2 (ALDH2), a key enzyme that detoxifies the ethanol metabolite acetaldehyde. However, how ALDH2 deficiency affects alcohol-related HCC remains unclear. ALDH2 polymorphisms were studied in 646 patients with viral hepatitis B (HBV) infection, who did or did not drink alcohol. A new model of HCC induced by chronic carbon tetrachloride (CCl4) and alcohol administration was developed and studied in 3 lines of Aldh2-deficient mice: including Aldh2 global knockout (KO) mice, Aldh2*1/*2 knock-in mutant mice, and liver-specific Aldh2 KO mice. We demonstrated that ALDH2 deficiency was not associated with liver disease progression but was associated with an increased risk of HCC development in cirrhotic patients with HBV who consumed excessive alcohol. The mechanisms underlying HCC development associated with cirrhosis and alcohol consumption were studied in Aldh2-deficient mice. We found that all 3 lines of Aldh2-deficient mice were more susceptible to CCl4 plus alcohol-associated liver fibrosis and HCC development. Furthermore, our results from in vivo and in vitro mechanistic studies revealed that after CCl4 plus ethanol exposure, Aldh2-deficient hepatocytes produced a large amount of harmful oxidized mitochondrial DNA via extracellular vesicles, which were then transferred into neighboring HCC cells and together with acetaldehyde activated multiple oncogenic pathways (JNK, STAT3, BCL-2, and TAZ), thereby promoting HCC. ALDH2 deficiency is associated with an increased risk of alcohol-related HCC development from fibrosis in patients and in mice. Mechanistic studies reveal a novel mechanism that Aldh2-deficient hepatocytes promote alcohol-associated HCC by transferring harmful oxidized mitochondrial DNA-enriched extracellular vesicles into HCC and subsequently activating multiple oncogenic pathways in HCC.

Explosive economic growth and increasing social openness in China over the last 30 years have significantly boosted alcohol consumption, and consequently, the incidence of alcoholic liver disease (ALD) in China has increased. Because the epidemiologic and clinical features of ALD in the Chinese population may differ from those of the Caucasian population, this review describes the epidemiology, pathogenesis, genetic polymorphisms, diagnosis, and treatment of ALD in the Chinese population. This updated knowledge of ALD in China provides information needed for a global understanding of ALD and may help in the development of useful strategies for reducing the global ALD burden.

Inflammation plays a role in the pathogenesis of acute-on-chronic liver failure (ACLF), however, whether there is a causal relationship between inflammation and ACLF remains unclear. A two-sample Mendelian randomization (MR) approach was used to investigate the causal relationship between systemic inflammatory regulators and ACLF. The study analyzed 41 cytokines and growth factors from 8,293 individuals extracted from a genome-wide association study (GWAS) meta-analysis database involving 253 ACLF cases and 456,095 controls. Our results showed that lower stem cell factor (SCF) levels, lower basic fibroblast growth factor (bFGF) levels and higher Interleukin-13 (IL-13) levels were associated with an increased risk of ACLF (OR = 0.486, 95% CI = 0.264–0.892, p = 0.020; OR = 0.323, 95% CI = 0.107–0.972, p = 0.044; OR = 1.492, 95% CI = 1.111–2.004, p = 0.008, respectively). In addition, genetically predicted ACLF did not affect the expression of systemic inflammatory regulators. Our results indicate that cytokines play a crucial role in the pathogenesis of ACLF. Further studies are needed to determine whether these biomarkers can be used to prevent and treat ACLF.

Hepatocellular carcinoma (HCC) is one of the important types of liver cancer. LncRNA is an important regulatory factor that regulates many biological processes such as tumor cells during tumorigenesis and metastasis. LINC00346 has been associated with various types of liver cancer, but its role and regulatory mechanism in HCC remain unclear. In our study, we found the LINC00356-miR-199a-3p-CDK1/CCNB1 axis through bioinformatics analysis. The expressions of LINC00356, miR-199a-3p, CDK1, and CCNB1 in HCC and normal hepatocytes were determined by qRT-PCR and WB. The results showed that LINC00356, CDK1 and CCNB1 were highly expressed in HCC, while miR-199a-3p was lowly expressed. Dual luciferase reporter gene assay, RIP and RNA-pull down assays demonstrated the targeted binding relationship of LINC00346-miR-199a-3p-CDK1/CCNB1. Overexpressing LINC00460 and silencing miR-199a-3p promoted cell invasion, inhibited apoptosis of HCC, and arrested the cell cycle in S phase while opposite results were obtained when silencing LINC00346, CDK1, and CCNB1. LINC00346 indirectly affects liver cancer by promoting the expression of CDK1/CCNB1 through competitive adsorption of miR-199a-3p. In addition, the study also demonstrated that overexpression of LINC00346 indirectly inhibited the expression of p53 and p21 proteins by promoting CDK1/CCNB1 expressions, thereby blocking the p53 signaling pathway. These results proved that LINC00346 could regulate the expression of CDK1/CCNB1 through the competitive adsorption of miR-199a-3p, thereby affecting the p53 signaling pathway and finally regulating the apoptosis, invasion and cell cycle of HCC cells. In conclusion, LINC00346 can be used as a tumor promoter and potential therapeutic target for HCC metastasis and prognosis.

AIMS: We aimed to develop new simple predictive models for significant fibrosis and inflammation in chronic hepatitis patients using routine laboratory parameters. METHODS: A total of 218 patients who had undergone liver biopsy were enrolled in our study. Among these, 116 had chronic hepatitis B, 65 had primary biliary cirrhosis, and 37 had autoimmune hepatitis. Patients were divided into two groups: absent-mild (S0-S1, G0-G1) and moderate-severe (S2-S4, G2-G4) according to the histologic severity of liver fibrosis and inflammation. All common demographics and routine laboratory parameters were analyzed. RESULTS: Red blood cell distribution width (RDW) and globulin values increased with progressive liver fibrosis and inflammation. After adjustment for other potent predictors, liver fibrosis was associated independently with RDW and platelet (odds ratio=0.976 and 1.487, respectively), whereas significant inflammation was associated independently with globulin, alanine aminotransferase, red blood cell, and platelet (odds ratio=1.153, 1.017, 0.392, and 1.487, respectively). The sensitivity and specificity of model A were 73.4 and 79.1% for the detection of significant liver fibrosis [area under the receiver-operating characteristic curve (AUROC)=0.81, P<0.001]. The sensitivity and specificity of model B were 75.9 and 88.9% for predicting advanced liver inflammation (AUROC=0.89, P<0.001). Compared with pre-existing indicators, model A achieved the highest AUROC (0.81, P<0.001) for liver fibrosis, whereas model B showed the highest AUROC (0.89, P<0.001) for liver inflammation. CONCLUSION: RDW may provide a useful clinical value for predicting liver fibrosis; meanwhile, globulin may provide a useful clinical value for predicting liver inflammation in chronic hepatitis patients with other markers.