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Early-onset hepatic fibrosis linking to a novel PYROXD2 mutation: A case report
Zhen-Yao Jiang, Rong-Qiang Liu, Meng-Juan Tang, Han-Dong Fan, Wen-Jun Yang, Ling Gong, Xiao-Xiao Mi, Jun-Ping Shi
Zhen-Yao Jiang, Rong-Qiang Liu, Jun-Ping Shi, Department of Infectious Diseases and Hepatology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou 310015, Zhejiang Province, China
Meng-Juan Tang, Han-Dong Fan, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou 310023, Zhejiang Province, China
Wen-Jun Yang, Department of Pathology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou 310015, Zhejiang Province, China
Ling Gong, Department of Infectious Disease and Hepatology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou 310015, Zhejiang Province, China
Ling Gong, Jun-Ping Shi, Zhejiang Key Laboratory of Medical Epigenetics, The Affiliated Hospital of Hangzhou Normal University, Hangzhou 310015, Zhejiang Province, China
Xiao-Xiao Mi, The institute of Translational Medicine, The Affiliated Hospital of Hangzhou Normal University, Hangzhou 310015, Zhejiang Province, China
Xiao-Xiao Mi, Jun-Ping Shi, Institute of Hepatology and Metabolic Diseases, Hangzhou Normal University, Hangzhou 310015, Zhejiang Province, China
Jun-Ping Shi, Institute of Translational Medicine, The Affiliated Hospital of Hangzhou Normal University, Hangzhou 310015, Zhejiang Province, China
Co-first authors: Zhen-Yao Jiang and Rong-Qiang Liu.
Co-corresponding authors: Xiao-Xiao Mi and Jun-Ping Shi.
Author contributions: Jiang ZY and Liu RQ contributed to patient recruitment and investigation, data collection, data analysis, and drafting of the initial manuscript; and they are co-first authors. Tang MJ and Fan HD were responsible for data collation, validation, and visualization; Yang WJ and Gong L oversaw data validation, patient follow-up, and participated in project supervision and guidance. Mi XX and Shi JP led the development of the research concept, secured research funding, supervised and guided the research project, and critically reviewed and revised the manuscript; and they are co-corresponding authors.
AI contribution statement: AI tools were utilized. We use DeepSeek-R1 for language polishing and improving the fluency. The entirety of the main text was not AI-generated. The content, ideas, and arguments are the original work of the authors. DeepSeek-R1 was used specifically for language polishing and improving the fluency and flow of the text. It was not used for data analysis, translation, or generating new content. AI did not participate in the design of the study or the interpretation of its results. No images were generated by AI; all figures were created by the authors using Adobe Illustrator.
Supported by the Huadong Medicine Joint Funds of the Zhejiang Provincial Natural Science Foundation of China, No. LHDMZ24H030001; the National Natural Science Foundation of China, No. 82470599; and Hangzhou Municipal Key Scientific Research Plan Project, No. 2025SZD1B09.
Informed consent statement: Written informed consent was obtained from the patient for publication of this report and any accompanying images.
Conflict-of-interest statement: All authors declare that they have no conflict of interest to disclose.
CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).
Corresponding author: Jun-Ping Shi, MD, Department of Infectious Diseases and Hepatology, The Affiliated Hospital of Hangzhou Normal University, No. 126 Wenzhou Road, Hangzhou 310015, Zhejiang Province, China.
20131004@hznu.edu.cn
Received: January 7, 2026
Revised: February 2, 2026
Accepted: February 27, 2026
Published online: May 27, 2026
Processing time: 139 Days and 13.9 Hours
BACKGROUND
Early-onset liver fibrosis is predominantly driven by inherited genetic mutations that disrupt critical metabolic or structural pathways in the liver. Pyridine nucleotide-disulfide oxidoreductase domain 2 (PYROXD2) (formerly named YueF) is a mitochondrial inner membrane/matrix-localized protein, regulating mitochondrial respiratory chain function. While emerging evidence highlights the role of PYROXD2 in mitochondrial redox homeostasis and respiratory chain integrity, its pathological contribution to early-onset liver fibrosis remains poorly characterized, particularly in the context of monogenic metabolic disorders and oxidative stress-mediated hepatocyte injury.
CASE SUMMARY
This report represents the first description of early-onset liver fibrosis in a patient harboring a heterozygous variant in the PYROXD2 gene. The patient presented with severe obesity, recurrent abnormalities in liver enzyme levels, and hyperuricemia, and demonstrated a suboptimal or absent response to hepatoprotective therapies. Whole-exome sequencing followed by Sanger validation identified a frameshift variant in the PYROXD2 gene (NM_032709.3, c.1082dupT, p.Phe361 Leu fs*50) in the affected patient. The variant was absent from population databases (gnomAD, 1000 Genomes) and had not been previously reported in the literature. Computational pathogenicity predictions consistently classified it as pathogenic. Protein modeling using SWISS-MODEL indicated that the variant induces deleterious conformational alterations.
CONCLUSION
Collectively, the present case highlights PYROXD2 as a novel candidate gene, contributing to early-onset liver fibrogenesis. The identification of this variant in the PYROXD2 gene in the patient demonstrates a previously unrecognized molecular pathway in juvenile hepatic fibrosis, with potential implications for personalized diagnosis and treatment.
Core Tip: For the first time, our study reports that a heterozygous frameshift mutation in the pyridine nucleotide-disulfide oxidoreductase domain 2 (PYROXD2) gene may underlie early-onset liver fibrosis. This variant impairs the function of mitochondrial oxidoreductases, ultimately triggering metabolic disturbances and the development of early liver fibrosis. Our findings uncover a novel pathogenic variation of PYROXD2 linking to early-onset liver fibrosis, thereby providing a new rationale for the genetic diagnosis of related disorders.
