Uridine diphosphate-glucose 6-dehydrogenase-mediated glucuronidation and its emerging role in gut-liver immune regulation.

This editorial builds on a recent study by Cao et al, which identified uridine diphosphate-glucose 6-dehydrogenase (UGDH) as a pro-tumorigenic enzyme in hepatocellular carcinoma (HCC). UGDH, a key catalyst in glucuronidation, promotes tumor growth and correlates with immunosuppressive features in the HCC microenvironment. Expanding on these findings, we explore broader implications of UGDH within the gut-liver axis. We propose that UGDH regulates immune tone not only through detoxification of bile acids and microbial products, but also by maintaining intestinal barrier integrity. Its dysregulation may impair glucuronidation, leading to bile acid accumulation, increased gut permeability, and microbial translocation, collectively promoting hepatic immune tolerance. Additionally, emerging evidence suggests that gut microbiota-derived metabolites can modulate hepatic UGDH expression, forming a bidirectional feedback loop between microbial ecology and liver metabolism. In this context, UGDH may act as a metabolic immune checkpoint, linking metabolic dysfunction with immune escape mechanisms such as programmed cell death ligand 1 upregulation and cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes pathway activation. Targeting UGDH could therefore help restore gut-liver immune balance and delay gastrointestinal cancer progression, especially in metabolic HCC. This editorial integrates metabolic, microbial, and immunological perspectives to support a novel translational framework.