Gut microbiota regulates the ALK5/NOX1 axis by altering glutamine metabolism to inhibit ferroptosis of intrahepatic cholangiocarcinoma cells

Qi Zhang; Jixiang Zhou; Denggao Zhai; Qin Jiang; Manyi Yang; Maojun Zhou

doi:10.1016/j.bbadis.2024.167152

Gut microbiota regulates the ALK5/NOX1 axis by altering glutamine metabolism to inhibit ferroptosis of intrahepatic cholangiocarcinoma cells

Biochim Biophys Acta Mol Basis Dis. 2024 Apr 5;1870(5):167152. doi: 10.1016/j.bbadis.2024.167152. Online ahead of print.

Authors

Qi Zhang¹, Jixiang Zhou², Denggao Zhai², Qin Jiang³, Manyi Yang⁴, Maojun Zhou⁵

Affiliations

¹ Department of Hepatobiliary and Pancreatic Surgery, Xiangya Hospital Central South University, Changsha 410008, China; International Joint Research Center of Minimally Invasive Endoscopic Technology Equipment & Standards, Xiangya Hospital, Central South University, Changsha 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China.
² Department of Hepatobiliary and Pancreatic Surgery, Xiangya Hospital Central South University, Changsha 410008, China.
³ Department of Ultrasonography, Xiangya Hospital, Central South University, Changsha 410008, China.
⁴ Department of Hepatobiliary and Pancreatic Surgery, NHC Key Laboratory of Nanobiological Technology, Xiangya Hospital, Central South University, Changsha 410008, China.
⁵ Department of Oncology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, Xiangya Hospital, Central South University, Changsha 410008, China. Electronic address: zhoumaojun@csu.edu.cn.

PMID: 38582012
DOI: 10.1016/j.bbadis.2024.167152

Abstract

Intrahepatic cholangiocarcinoma (ICC) is a kind of hepatobiliary tumor that is increasing in incidence and mortality. The gut microbiota plays a role in the onset and progression of cancer, however, the specific mechanism by which the gut microbiota acts on ICC remains unclear. In this study, feces and plasma from healthy controls and ICC patients were collected for 16S rRNA sequencing or metabolomics analysis. Gut microbiota analysis showed that gut microbiota abundance and biodiversity were altered in ICC patients compared with controls. Plasma metabolism analysis showed that the metabolite glutamine content of the ICC patient was significantly higher than that of the controls. KEGG pathway analysis showed that glutamine plays a vital role in ICC. In addition, the use of antibiotics in ICC animals further confirmed that changes in gut microbiota affect changes in glutamine. Further experiments showed that supplementation with glutamine inhibited ferroptosis and downregulated ALK5 and NOX1 expression in HuCCT1 cells. ALK5 overexpression or NOX1 overexpression increased NOX1, p53, PTGS2, ACSL4, LPCAT3, ROS, MDA and Fe²⁺ and decreased FTH1, SLC7A11 and GSH. Knockdown of NOX1 suppressed FIN56-induced ferroptosis. In vivo, supplementation with glutamine promoted tumor growth. Overexpression of ALK5 repressed tumor growth and induced ferroptosis in nude mice, which could be reversed by the addition of glutamine. Our results suggested that the gut microbiota altered glutamine metabolism to inhibit ferroptosis in ICC by regulating the ALK5/NOX1 axis.

Keywords: ALK5/NOX1; Ferroptosis; Glutamine; Gut microbiota; Intrahepatic cholangiocarcinoma.