PD‐L1 is a critical checkpoint that protects tissues from autoimmune injury. Nevertheless, the role of PD‐L1 in nonalcoholic fatty liver disease‐ (NAFLD‐) induced liver damage is still unclear. In this study, we examined the role and mechanism of PD‐L1 expression on NAFLD‐induced liver damage in vitro and in vivo. PD‐L1 expression in the livers from patients with NAFLD, and LO2 cells treated by FFA, was significantly increased. FFA triggers a large amount of ROS (generated from NOX4 and damaged mitochondria), promoting the ZNF24 expression and suppressing ZN24 sumoylation, both of which enhance the PD‐L1 transcription and expression. The knockdown of PD‐L1 increases CD8 + T cells’ damage to FFA‐treated LO2 cells, while its upregulation limits the liver injury in NAFLD models. Collectively, we demonstrate that FFA promotes PD‐L1 expression through the ROS/ZNF24 pathway and suppresses UBE2I‐mediated ZNF24 sumoylation to enhance its transcriptional activity of PD‐L1. PD‐L1 upregulation limits FFA‐induced injury of hepatocytes in vitro and in vivo.

Background: It remains unclear whether the addition of non‐selective beta‐blockers (NSBB) provides further benefit after combined use of tissue adhesive and endoscopic variceal ligation for bleeding gastroesophageal varices. Objective: This is the first cohort study comparing the secondary prophylactic efficacy of adding NSBB to combined endoscopic treatment in cirrhotic patients with gastric varices (without inclusion of isolated gastric varices [IGVs], which are rare in patients with cirrhosis without splanchnic thrombosis). Methods: We retrospectively analyzed two matched large cohorts of cirrhotic patients with gastric varices who received combined endoscopic treatment and were assigned to receive NSBB treatment or not as secondary prophylaxis. Further sub‐analyses were performed. The 5‐year overall survival and rebleeding rates were compared. Results: A total of 490 patients were enrolled, 130 of whom took NSBB. After propensity score matching (PSM), both groups comprised 130 patients. No significant difference between the NSBB and non‐NSBB groups was observed regarding 5‐year survival (87.40% vs. 83.64%, HR 0.62, 95% CI 0.33–1.17), while NSBB decreased the 5‐year rebleeding rate from 45.7% to 30.64% (HR 0.57, 95% CI 0.39–0.82). The same was true when comparing the 2 groups after PSM. NSBB (HR 0.54, 95% CI 0.37–0.79) and splenectomy (HR 0.65, 95% CI 0.44–0.96) independently reduced rebleeding but did not affect survival. In patients without splenectomy, NSBB treatment improved survival (HR 0.43, 95% CI 0.21–0.89) and reduced rebleeding (HR 0.52, 95% CI 0.34–0.78). Conclusion: We show for the first time that adding NSBB to combined endoscopic therapy significantly reduced recurrent variceal bleeding in cirrhotic patients but did not improve overall survival, except for patients without splenectomy. The addition of NSBB for patients receiving combined endoscopic treatment of gastroesophageal varices provides benefits but does not prolong overall survival.

Background: Activated hepatic stellate cells are the most critical cell responsible for liver fibrosis. In liver fibrogenesis, platelet-derived growth factor is the most prominent mitogen for hepatic stellate cells. This study aims to explore the potential of gadolinium (Gd)-labeled cyclic peptides (pPB) targeted to platelet-derived growth factor receptor-β (PDGFR-β) as a magnetic resonance imaging (MRI) radiotracer to identify the progress of liver fibrosis by imaging hepatic PDGFR-β expression. Results: Hepatic PDGFR-β expression level was found to be paralleled with the severity of liver fibrosis, which was increased with the progression of fibrosis and reduced with the regression. Majority of cells expressing PDGFR-β was determined to be activated hepatic stellate cells in fibrotic livers. Culture-activated human hepatic stellate cells expressed abundant PDGFR-β, and FITC-labeled pPB could bind to human hepatic stellate cells in a concentration and time dependent manner. With Gd-labeled pPB as a tracer, an MRI modality demonstrated that the relative hepatic T1-weighed MR signal value was increased progressively along with severity of hepatic fibrosis and reduced with the remission. Conclusion: Hepatic PDGFR-β expression reflects the progress of hepatic fibrosis, and MR imaging using Gd-labeled pPB as a tracer may distinguish different stages of liver fibrosis in mice.