Metabolic Diversion from Geranylgeranoic Acid to 2,3-Dihydrogeranylgeranoic Acid in Hepatic Tumor Surveillance
Geranylgeranoic acid (GGA) is an endogenous acyclic diterpenoid metabolite of the mevalonate pathway that has been implicated in programmed cell death in hepatoma cells and may contribute to the elimination of premalignant hepatocytes. Recent metabolomic studies have identified 2,3-dihydrogeranylgeranoic acid (2,3-diGGA), an α-saturated derivative of GGA with reduced cell-death-inducing activity compared with GGA. This concise review examines the hypothesis that diversion of bioactive GGA toward 2,3-diGGA formation represents a metabolic shift that may attenuate hepatic tumor surveillance and influence hepatocellular carcinoma susceptibility. The review summarizes current evidence for endogenous GGA biosynthesis through the mevalonate pathway, MAO-B- and CYP3A4-associated GGA formation, and the tissue- and age-associated distribution of GGA and 2,3-diGGA. It also discusses the proposed 2,3-diGGA-forming activity, whose molecular identity remains unknown, and evaluates the potential utility of the GGA/2,3-diGGA ratio as a candidate biomarker. Finally, future experimental strategies are outlined to identify the responsible enzyme, clarify causality in cellular and animal models, and validate this metabolic framework in human liver tissues, chronic liver disease cohorts, and HCC-associated settings.