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©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
Clinical significance of citrullinated glial fibrillary acidic protein in predicting outcomes in hepatocellular carcinoma
Yoon Ah Cho, Dong Woo Shin, Mo-Jong Kim, Ji-Won Park, Ji-Young Choe, Jung-Woo Lee, Sung-Hoon Moon, Akihito Ishigami, Eun Kyoung Choi, Sung-Eun Kim
Yoon Ah Cho, Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea
Dong Woo Shin, Ji-Won Park, Sung-Hoon Moon, Sung-Eun Kim, Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang 14068, Gyeonggi-do, South Korea
Mo-Jong Kim, Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
Ji-Young Choe, Anatomic Pathology Reference Lab, Seegene Medical Foundation, Seoul 04805, South Korea
Jung-Woo Lee, Department of Surgery, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang 14068, South Korea
Akihito Ishigami, Molecular Regulation of Aging, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo 173-0015, Japan
Eun Kyoung Choi, Department of Biomedical Gerontology, Graduate School of Hallym University, Chuncheon 24252, South Korea
Author contributions: Cho YA was responsible for visualization; Cho YA and Kim SE were responsible for the conceptualization and the original drafting; Shin DW, Kim MJ, Ishigami A, Choi EK, and Kim SE were responsible for the methodology; Cho YA, Kim MJ, Park JW, and Choe JY were responsible for the data collection; Cho YA and Choe JY were responsible for the construction of the tissue microarray; Cho YA, Lee JW, and Kim SE were responsible for data acquisition and analysis; Shin DW and Moon SH were responsible for the software; Cho YA, Choi EK, and Kim SE were responsible for writing-review and editing; Choi EK and Kim SE supervised the study. All authors approved the final version of the manuscript before submission.
Supported by Korean Society of Gastroenterology funded by Korea Research Foundation of Internal Medicine, No. KSG-2022-02.
Institutional review board statement: The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of Hallym University Sacred Heart Hospital (No. HALLYM202105009002-HE002).
Informed consent statement: Given the retrospective design of the study using anonymized clinical data, the requirement for informed consent was waived.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
STROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement-checklist of items.
Data sharing statement:
No additional data are available.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
https://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Sung-Eun Kim, MD, PhD, Professor, Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, 22 Gwanpyeong-ro 170 beon-gil, Dongan-gu, Anyang 14068, Gyeonggi-do, South Korea.
sekim@hallym.or.kr
Received: June 23, 2025
Revised: July 29, 2025
Accepted: November 12, 2025
Published online: December 15, 2025
Processing time: 173 Days and 23.8 Hours
BACKGROUND
Citrullination is a post-translational modification mediated by calcium-dependent peptidylarginine deiminases that results in notable changes in protein structure and function. Glial fibrillary acidic protein (GFAP), which is highly vulnerable to peptidylarginine deiminases-mediated modification, has been found to be elevated in activated hepatic stellate cells, with GFAP-positive hepatic stellate cells and myofibroblasts accumulating within and around areas of hepatic fibrosis. Although recent studies have shown that the expression of citrullinated GFAP (cit-GFAP) increases during hepatic fibrosis, its expression pattern and functional roles in hepatocellular carcinoma (HCC) remain unclear.
AIM
To determine whether cit-GFAP expression influences the recurrence and survival of patients undergoing hepatic resection for HCC.
METHODS
We retrospectively analyzed 169 patients with HCC who underwent hepatic resection. Based on the immunohistochemical staining of resected specimens, the enrolled patients were stratified into two groups according to cit-GFAP expression: Low (-/1 +) or high (2 +/3 +) levels of expression. Kaplan-Meier survival curves were constructed to assess overall survival and recurrence-free survival, and comparisons between groups were performed using the log-rank test.
RESULTS
The median follow-up duration was 33 months (range, 1-183). High cit-GFAP expression, identified in 81 patients (48.2%), was significantly associated with male sex, hepatitis B virus positivity, and higher Edmonson-Steiner grade. No associations were found between age, diabetes, hypertension, cirrhosis, Child-Pugh classification, major portal vein invasion, hematological or biochemical parameters, tumor size, or number. Patients exhibiting high cit-GFAP expression demonstrated significantly poorer overall survival. Multivariate Cox analysis identified large tumor size (hazard ratio: 2.967; 95% confidence interval: 1.097-8.024; P = 0.032) and high cit-GFAP expression (hazard ratio: 2.753; 95% confidence interval: 1.015-7.464; P = 0.047) as independent predictors of poor postoperative survival. Although recurrence rates were high in patients with high cit-GFAP expression, the difference was not statistically significant.
CONCLUSION
Following curative resection in patients with HCC, high cit-GFAP expression may serve as a potential prognostic biomarker, although further validation through independent cohort studies is warranted.
Core Tip: High citrullinated-glial fibrillary acidic protein (cit-GFAP) expression is significantly associated with increased mortality in patients with hepatocellular carcinoma following surgical resection. Multivariate Cox regression analysis identified larger tumor size and elevated cit-GFAP expression as independent predictors of poor postoperative survival. These findings suggest the potential prognostic value of cit-GFAP levels, although further validation through independent cohort studies is necessary to confirm its clinical utility as a biomarker.
