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World J Gastroenterol. Sep 28, 2026; 32(36): 119990
Published online Sep 28, 2026. doi: 10.3748/wjg.119990
AKT-eNOS-NO pathway mediates spontaneous portosystemic shunts and therapeutic efficacy of SC79 in cirrhosis
Qiao Ke, Zhi-Ting Guo, Jian He, Xin-Hui Huang, Xiao-Juan Lei, Qiu-Yu Zhuang, Yang Zhou, Ling Li, Ying-Chao Wang, Jing-Feng Liu, Wu-Hua Guo
Qiao Ke, Jian He, Xin-Hui Huang, Xiao-Juan Lei, Ling Li, Wu-Hua Guo, Department of Interventional Radiology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, Fujian Province, China
Qiao Ke, Department of Hepatopancreatobiliary Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine, Chinese Academy of Sciences, Hangzhou 310022, Zhejiang Province, China
Zhi-Ting Guo, Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
Qiu-Yu Zhuang, Yang Zhou, Ying-Chao Wang, The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, Fujian Province, China
Jing-Feng Liu, Department of Hepatopancreatobiliary Surgery, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou 350014, Fujian Province, China
Co-first authors: Qiao Ke and Zhi-Ting Guo.
Co-corresponding authors: Jing-Feng Liu and Wu-Hua Guo.
Author contributions: Ke Q and Guo ZT contributed equally to this work and are co-first authors; Ke Q and Guo ZT designed and performed the main experiments, analyzed the data, and drafted the manuscript; He J participated in animal experiments and data analysis; Huang XH, Lei XJ, Zhuang QY, Zhou Y, and Li L were involved in clinical sample collection, patient follow-up, and data curation; Wang YC participated in data interpretation and critically revised the manuscript; Liu JF and Guo WH conceived and supervised the study, critically revised the manuscript, and contributed equally as co-corresponding authors; and all authors contributed to the article and approved the final version of the manuscript.
AI contribution statement: The main text and the response to reviewers were prepared by the authors. ChatGPT was used only for language polishing. No AI tool was used for translation, data analysis, or data interpretation.
Supported by the Joint Funds for the Innovation of Science and Technology of Fujian Province, China, No. 2021Y9033; the Key Clinical Specialty Discipline Construction Program of Fuzhou, Fujian Province, China; and the Natural Science Foundation of Fujian Province, China, No. 2023J011463.
Institutional review board statement: Human studies were performed in compliance with the principles of the Declaration of Helsinki and were approved by the Ethics Committee of Mengchao Hepatobiliary Hospital, Fujian Medical University (Approval No. 2024_109_01).
Institutional animal care and use committee statement: All animal procedures were conducted in accordance with institutional guidelines and were approved by the Laboratory Animal Welfare and Ethics Committee of Mengchao Hepatobiliary Hospital, Fujian Medical University (Approval No. MCHH-AEC-2023-12).
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.
Corresponding author: Wu-Hua Guo, MD, PhD, Professor, Department of Interventional Radiology, Mengchao Hepatobiliary Hospital of Fujian Medical University, No. 66 Jintang Road, Fuzhou 350025, Fujian Province, China.
guowuhua@aliyun.com
Received: February 12, 2026
Revised: April 3, 2026
Accepted: May 12, 2026
Published online: September 28, 2026
Processing time: 191 Days and 0.7 Hours
BACKGROUND
Spontaneous portosystemic shunts (SPSS) are common in patients with cirrhosis and portal hypertension; however, their prognostic significance and underlying mechanisms remain poorly defined.
AIM
To investigate the prognostic impact of SPSS in hepatitis B virus (HBV)-related cirrhosis and to explore the molecular mechanisms underlying its development.
METHODS
We retrospectively analyzed a nationwide multicenter cohort of patients with HBV-related cirrhosis from 2017 to 2021. Patients were stratified by imaging findings into SPSS and non-SPSS groups, and outcomes, including hepatic decompensation events and mortality, were compared between groups. Proteomic profiling of liver tissue and metabolomic profiling of serum were performed to identify differentially expressed molecules and enriched pathways. Mechanistic validation was conducted in a rat model of cirrhosis with SPSS.
RESULTS
Patients with SPSS exhibited more severe hepatic dysfunction and had higher rates of hepatic decompensation, including esophagogastric variceal bleeding, portal vein thrombosis, hepatic encephalopathy, ascites, and hepatocellular carcinoma, as well as higher mortality, than patients without SPSS. Multi-omics analyses identified 100 differentially expressed proteins and 54 metabolites enriched in 11 signaling pathways, notably the AKT-eNOS-nitric oxide (NO) axis, a key regulator of angiogenesis. In vivo, pharmacologic activation of AKT with SC79 increased hepatic p-AKT and p-eNOS levels, elevated NO levels, reduced the incidence of SPSS, attenuated cirrhosis severity, and decreased the expression of angiogenesis-related markers.
CONCLUSION
SPSS is associated with poor prognosis in HBV-related cirrhosis. Dysregulation of the AKT-eNOS-NO pathway may contribute to SPSS formation and represents a potential therapeutic target.
Core Tip: Spontaneous portosystemic shunts (SPSS) are strongly associated with adverse outcomes in hepatitis B virus-related cirrhosis, including more frequent decompensation and higher mortality. By integrating multicenter clinical data with proteomic, metabolomic, and animal studies, this work identifies dysregulation of the AKT-eNOS-nitric oxide pathway as a potential mechanism underlying SPSS formation. Pharmacologic activation of AKT with SC79 reduced the incidence of SPSS and alleviated cirrhosis severity in vivo, suggesting that this pathway may represent a promising therapeutic target in cirrhosis with portal hypertension.
