Background: There is still a lack of knowledge on the association between cholecystectomy and liver disease. This systematic review and meta-analysis was conducted to summarize the available evidence on the association of cholecystectomy with liver disease and quantify the magnitude of the risk of liver disease after cholecystectomy. Methods: PubMed, Embase, Web of Science, and Cochrane Library were searched systematically from database inception to January 2023 to identify eligible studies that evaluated the association between cholecystectomy and the risk of liver disease. Meta-analysis was conducted to obtain a summary odds ratio (OR) and 95% confidence interval (CI) using a random-effects model. Results: We identified 20 studies with a total of 27,320,709 individuals and 283,633 liver disease cases. Cholecystectomy was associated with an increased risk of liver disease (OR 1.63, 95% CI 1.34-1.98). In particular, cholecystectomy was found to be significantly associated with a 54% increased risk of nonalcoholic fatty liver disease (OR 1.54, 95% CI 1.18-2.01), a 173% increased risk of cirrhosis (OR 2.73, 95% CI 1.81-4.12), and a 46% increased risk of primary liver cancer (OR 1.46, 95% CI 1.18-1.82). Conclusions: There is an association between cholecystectomy and the risk of liver disease. Our results suggest that strict surgical indications should be implemented to reduce unnecessary cholecystectomy. Additionally, the routine assessment of liver disease is necessary for patients with a history of cholecystectomy. More prospective large-sample studies are required for better estimates of the risk. Export

Dimethyl fumarate (DMF) exerts cytoprotective effects via antioxidant pathway activation. Whether it modulates antitumor immunity through novel cell death forms remains unclear. GSH/GSSG levels were measured in HCC and adjacent tissues using assay kits, with FDX1 and GCLM expression detected by IHC. Cuproptosis-related proteins (NRF2, FDX1, LIAS) and DLAT oligomerization were assessed by western blotting and immunofluorescence in HCC cells. Intracellular GSH, glutamate, Cu ²⁺ , and γ-GCS activity were measured biochemically. Cell viability was determined by CCK-8. CD8 ⁺ T cells cocultured with HCC cells were analyzed for GZMB, IFN-γ, and TNF-α by flow cytometry; cytotoxicity was evaluated by LDH release. HCC tissues exhibited elevated GSH, downregulated FDX1, and upregulated GCLM compared with adjacent tissues. Elesclomol-Cu ²⁺ (ES-Cu) induced cuproptosis, upregulating NRF2, downregulating FDX1 and LIAS, promoting DLAT oligomerization, and causing GSH depletion and Cu ²⁺ accumulation; GSH-MEE reversed these effects. DMF inhibited GSH metabolism, evidenced by NRF2 downregulation, decreased GSH, increased GSSG, and suppressed γ-GCS activity. Mechanistically, DMF promoted cuproptosis via NRF2 inhibition, which was reversed by NRF2 overexpression. DMF-induced cuproptosis enhanced TNF-α, IFN-γ, and GZMB expression and increased CD8 ⁺ T-cell cytotoxicity; the copper chelator tetrathiomolybdate blocked these effects. DMF induces cuproptosis by modulating GSH metabolism, thereby activating CD8 ⁺ T-cell-mediated anti-HCC immunity. This offers potential targets for novel combination therapeutic strategies.