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

Abstract

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.

Keywords: Uridine diphosphate-glucose 6-dehydrogenase; Glucuronidation; Gut-liver axis; Hepatocellular carcinoma; Immune microenvironment

Core Tip: Uridine diphosphate-glucose 6-dehydrogenase (UGDH), a key metabolic enzyme involved in glucuronidation, is increasingly recognized for its role in hepatocellular carcinoma progression. Recent studies have revealed that dysregulated UGDH contributes not only to metabolic reprogramming but also to immune suppression by disrupting bile acid detoxification and facilitating microbial translocation from the gut. This editorial highlights the dual function of UGDH as both a metabolic and immune modulator, and introduces a novel hypothesis that positions UGDH as a potential checkpoint within the gut-liver immune axis. Understanding this interplay could lead to new therapeutic strategies targeting metabolic-immune cross-talk in gastrointestinal oncology.