Despite therapy with potent antiviral agents, chronic hepatitis B (CHB) patients remain at high risk of hepatocellular carcinoma (HCC). While metabolites have been rediscovered as active drivers of biological processes including carcinogenesis, the specific metabolites modulating HCC risk in CHB patients are largely unknown. Here, we demonstrate that baseline plasma from CHB patients who later developed HCC during follow-up exhibits growth-promoting properties in a case-control design nested within a large-scale, prospective cohort. Metabolomics analysis reveals a reduction in long-chain acylcarnitines (LCACs) in the baseline plasma of patients with HCC development. LCACs preferentially inhibit the proliferation of HCC cells in vitro at a physiological concentration and prevent the occurrence of HCC in vivo without hepatorenal toxicity. Uptake and metabolism of circulating LCACs increase the intracellular level of acetyl coenzyme A, which upregulates histone H3 Lys14 acetylation at the promoter region of KLF6 gene and thereby activates KLF6/p21 pathway. Indeed, blocking LCAC metabolism attenuates the difference in KLF6/p21 expression induced by baseline plasma of HCC/non-HCC patients. The deficiency of circulating LCACs represents a driver of HCC in CHB patients with viral control. These insights provide a promising direction for developing therapeutic strategies to reduce HCC risk further in the antiviral era.

Objective To investigate the inhibitory effects of oridonin combined with gemcitabine on pancreatic cancer SW1990 cells in vitro, and the potential mechanisms thereof. Methods The pancreatic cancer SW1990 cells were treated with vehicle alone and various concentrations (10,20,40,80 and160μmol/L) of oridonin, followed by 24, 48 and 72 h cell culture. Effects of oridonin on cell proliferation were determined by using a CCK-8 kit. SW1990 cells were treated with oridonin (40μmol/L) and gemcitabine (20μmol/L) alone or together for 48 h, and the untreated cells were used as the con-trol. The cell survival rate was detected by CCK-8 assay. Apoptosis induction was assessed by using Annexin V-FITC kit. Semi-quantitative RT-PCR was used to examine the changes of NF-κB mRNA and XIAP mRNA expressions. Results Oridonin inhibited the growth of pancreatic cancer SW1990 cells in a dose-and time-dependent manner. Compared with the other groups, the cell survival rate was significantly lower in the combination group (P<0.05). Oridonin combined with gemcitabine induced a higher percentage of apoptosis in pancreatic cancer cells than that of oridonin or gemcitabine alone (P<0.05). Moreover, the expressions of NF-κB and XIAP mRNA in pancreatic carcinoma cells were obviously down-regu-lated in combination group (P<0.05). Conclusion Oridonin can enhance the antitumor effect of gemcitabine on pancreatic cancer in vitro, which may be related to through the down-regulation of NF-κB and its downstream of XIAP, and then induc-ing cell apoptosis in pancreatic cancer.