Alistipes-derived monomethyl branched-chain fatty acid iso-15:0 suppresses hepatocellular carcinoma progression by inhibiting Gβγ/PI3K/AKT signaling

The role of gut microbiota and their metabolites in the progression of hepatocellular carcinoma (HCC) has garnered increasing attention. Although Alistipes, a genus frequently reported as a beneficial bacterium, has been associated with antitumor effects and enhanced efficacy of cancer therapies, its specific functions and underlying mechanisms in HCC remain poorly defined. In this study, 16S rDNA sequencing revealed a marked decrease in the abundance of Alistipes in fecal samples from HCC patients compared to healthy controls, a finding that was also observed in HCC mouse models. Additionally, iso-15:0, an important fatty acid metabolite derived from Alistipes, was found to be significantly reduced in the feces of both HCC patients and HCC mouse models. Functional experiments demonstrated that iso-15:0 effectively suppresses the proliferation and migration of HCC cells in vitro and in vivo. Mechanistically, iso-15:0 inhibits the activation of the PI3K/AKT signaling pathway by interfering with G protein-coupled receptor (GPCR) downstream signaling, specifically through the Gβγ subunits. To further explore the potential for the clinical application of iso-15:0, we have developed a biomimetic nanodelivery system (3R/RGD/M1@iso-15:0 LNP) that markedly improves the delivery efficiency and therapeutic efficacy of iso-15:0 in vivo. Our findings elucidate for the first time that iso-15:0, derived from Alistipes, suppresses HCC progression by restricting the Gβγ-PI3K/AKT signaling axis, highlighting its potential as a novel therapeutic strategy for HCC.