Endogenous and Dietary Geranylgeranoic Acid: A Mini Review on Its Role in Hepatic Tumor Suppression

Geranylgeranoic acid (GGA) is an acyclic diterpenoid that functions as a ligand for retinoic acid receptors (RAR and RXR) and promotes differentiation in human hepatoma cell lines. Unlike natural retinoids, GGA induced apoptotic-like cell death at micromolar concentrations. In the early 2000s, GGA was identified as a naturally occurring diterpenoid in plants, including turmeric (Curcuma longa). Based on its chemical structure, GGA is presumed to be biosynthesized from the metabolic intermediate geranylgeranyl pyrophosphate (GGPP), which is derived from either the mevalonate or non-mevalonate pathways. GGPP is dephosphorylated to geranylgeraniol (GGOH), which is subsequently oxidized in two steps to produce GGA. Our research further demonstrated that GGA is endogenously synthesized in mammals via the MVA pathway, and that monoamine oxidase B and cytochrome P450 enzyme CYP3A4 are involved in its hepatic metabolism. Notably, in a spontaneous hepatoma mouse model, hepatic GGA levels were markedly depleted by 23 months of age in mice. However, oral supplementation with GGA starting at 11 months significantly suppressed hepatocellular carcinoma development. These findings suggest that age-related declines in endogenous GGA levels may be associated with tumorigenesis and that dietary supplementation may contribute to cancer prevention. This review outlines the biochemical pathways of GGA biosynthesis, its dietary origins, and its known biological functions, with particular emphasis on its tumor-suppressive effects in animal models. We also discuss the potential nutritional relevance of GGA-containing foods in disease prevention. By integrating previous findings with recent analytical data, we propose future research directions to clarify the physiological roles of GGA and its potential applications in functional-food science.