Alistipes-derived monomethyl branched-chain fatty acid iso-15:0 suppresses hepatocellular carcinoma progression by inhibiting Gβγ/PI3K/AKT signaling.
9 affiliations
- 1School of Medicine, Department of Medical Oncology of Chongqing University Cancer Hospital, Chongqing University, Chongqing, 400030, China.
- 2Chongqing Key Laboratory for the Mechanism and Intervention of Cancer Metastasis, Chongqing, 400030, China.
- 3Key Laboratory of Chongqing Education Commission of China for Cancer Immunometabolism Translational Research, Chongqing, 400030, China.
- 4School of Medicine, Department of Medical Oncology of Chongqing University Cancer Hospital, Chongqing University, Chongqing, 400030, China. [email protected].
- 5Chongqing Key Laboratory for the Mechanism and Intervention of Cancer Metastasis, Chongqing, 400030, China. [email protected].
- 6Key Laboratory of Chongqing Education Commission of China for Cancer Immunometabolism Translational Research, Chongqing, 400030, China. [email protected].
- 7School of Medicine, Department of Medical Oncology of Chongqing University Cancer Hospital, Chongqing University, Chongqing, 400030, China. [email protected].
- 8Chongqing Key Laboratory for the Mechanism and Intervention of Cancer Metastasis, Chongqing, 400030, China. [email protected].
- 9Key Laboratory of Chongqing Education Commission of China for Cancer Immunometabolism Translational Research, Chongqing, 400030, China. [email protected].
Abstract
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.
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BibTeX
@article{he2026alistipesderived,
title = {{Alistipes-derived monomethyl branched-chain fatty acid iso-15:0 suppresses hepatocellular carcinoma progression by inhibiting Gβγ/PI3K/AKT signaling.}},
author = {Juan He and Yu Chen and Liwen Kuang and Yang Xiao and Jiongming Chen and Xudong Liu and Jiangang Zhang and Ziyi Li and Dongqin Zhou and Miaoyu Song and Yi Yi and Danyang Li and Haili Shang and Nan Zhang and Ran Ren and Yu Zhou and Juan Lei and Huakan Zhao and Yongsheng Li},
journal = {Molecular biomedicine},
year = {2026},
month = oct,
doi = {10.1186/s43556-026-00622-1},
url = {https://europepmc.org/article/MED/42873452},
note = {CC BY},
}
RIS
TY - JOUR
TI - Alistipes-derived monomethyl branched-chain fatty acid iso-15:0 suppresses hepatocellular carcinoma progression by inhibiting Gβγ/PI3K/AKT signaling.
AU - Juan He
AU - Yu Chen
AU - Liwen Kuang
AU - Yang Xiao
AU - Jiongming Chen
AU - Xudong Liu
AU - Jiangang Zhang
AU - Ziyi Li
AU - Dongqin Zhou
AU - Miaoyu Song
AU - Yi Yi
AU - Danyang Li
AU - Haili Shang
AU - Nan Zhang
AU - Ran Ren
AU - Yu Zhou
AU - Juan Lei
AU - Huakan Zhao
AU - Yongsheng Li
PY - 2026
DA - 2026/10/14
JO - Molecular biomedicine
DO - 10.1186/s43556-026-00622-1
UR - https://europepmc.org/article/MED/42873452
AB - 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.
SN - 2662-8651
ER -