Integrative proteo-transcriptomic characterization of advanced fibrosis in chronic liver disease across etiologies

Hong Yang; Dila Atak; Meng Yuan; Mengzhen Li; Ozlem Altay; Elif Demirtas; Ibrahim Batuhan Peltek; Burge Ulukan; Buket Yigit; Tarik Sipahioglu; María Bueno Álvez; Lingqi Meng; Bayram Yüksel; Hasan Turkez; Hale Kirimlioglu; Burcu Saka; Cihan Yurdaydin; Murat Akyildiz; Murat Dayangac; Mathias Uhlen; Jan Boren; Cheng Zhang; Adil Mardinoglu; Mujdat Zeybel

doi:10.1016/j.xcrm.2025.101935

Integrative proteo-transcriptomic characterization of advanced fibrosis in chronic liver disease across etiologies

Hong Yang, Dila Atak, Meng Yuan, Mengzhen Li, Ozlem Altay, Elif Demirtas, Ibrahim Batuhan Peltek, Burge Ulukan, Buket Yigit, Tarik Sipahioglu, María Bueno Álvez, Lingqi Meng, Bayram Yüksel, Hasan Turkez, Hale Kirimlioglu, Burcu Saka, Cihan Yurdaydin, Murat Akyildiz, Murat Dayangac, Mathias UhlenJan Boren, Cheng Zhang, Adil Mardinoglu^*, Mujdat Zeybel^*

^*Corresponding author for this work

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Abstract

Chronic hepatic injury and inflammation from various causes can lead to fibrosis and cirrhosis, potentially predisposing to hepatocellular carcinoma. The molecular mechanisms underlying fibrosis and its progression remain incompletely understood. Using a proteo-transcriptomics approach, we analyze liver and plasma samples from 330 individuals, including 40 healthy individuals and 290 patients with histologically characterized fibrosis due to chronic viral infection, alcohol consumption, or metabolic dysfunction-associated steatotic liver disease. Our findings reveal dysregulated pathways related to extracellular matrix, immune response, inflammation, and metabolism in advanced fibrosis. We also identify 132 circulating proteins associated with advanced fibrosis, with neurofascin and growth differentiation factor 15 demonstrating superior predictive performance for advanced fibrosis(area under the receiver operating characteristic curve [AUROC] 0.89 [95% confidence interval (CI) 0.81–0.97]) compared to the fibrosis-4 model (AUROC 0.85 [95% CI 0.78–0.93]). These findings provide insights into fibrosis pathogenesis and highlight the potential for more accurate non-invasive diagnosis.

Original language	English
Article number	101935
Journal	Cell Reports Medicine
Volume	6
Issue number	2
Early online date	18 Feb 2025
DOIs	https://doi.org/10.1016/j.xcrm.2025.101935
Publication status	Published - 18 Feb 2025

Keywords

chronic liver disease
liver fibrosis
multi-omics
non-invasive
systems biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Integrative proteo-transcriptomic characterization_YANG_Publishedonline18February2025_GOLD_VoR (CC BY)Final published version, 6.76 MBLicence: CC BY

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Yang, H., Atak, D., Yuan, M., Li, M., Altay, O., Demirtas, E., Peltek, I. B., Ulukan, B., Yigit, B., Sipahioglu, T., Álvez, M. B., Meng, L., Yüksel, B., Turkez, H., Kirimlioglu, H., Saka, B., Yurdaydin, C., Akyildiz, M., Dayangac, M., ... Zeybel, M. (2025). Integrative proteo-transcriptomic characterization of advanced fibrosis in chronic liver disease across etiologies. Cell Reports Medicine, 6(2), Article 101935. https://doi.org/10.1016/j.xcrm.2025.101935

@article{fe6643cc99874111aaa9152e5e11ed68,

title = "Integrative proteo-transcriptomic characterization of advanced fibrosis in chronic liver disease across etiologies",

abstract = "Chronic hepatic injury and inflammation from various causes can lead to fibrosis and cirrhosis, potentially predisposing to hepatocellular carcinoma. The molecular mechanisms underlying fibrosis and its progression remain incompletely understood. Using a proteo-transcriptomics approach, we analyze liver and plasma samples from 330 individuals, including 40 healthy individuals and 290 patients with histologically characterized fibrosis due to chronic viral infection, alcohol consumption, or metabolic dysfunction-associated steatotic liver disease. Our findings reveal dysregulated pathways related to extracellular matrix, immune response, inflammation, and metabolism in advanced fibrosis. We also identify 132 circulating proteins associated with advanced fibrosis, with neurofascin and growth differentiation factor 15 demonstrating superior predictive performance for advanced fibrosis(area under the receiver operating characteristic curve [AUROC] 0.89 [95% confidence interval (CI) 0.81–0.97]) compared to the fibrosis-4 model (AUROC 0.85 [95% CI 0.78–0.93]). These findings provide insights into fibrosis pathogenesis and highlight the potential for more accurate non-invasive diagnosis.",

keywords = "chronic liver disease, liver fibrosis, multi-omics, non-invasive, systems biology",

author = "Hong Yang and Dila Atak and Meng Yuan and Mengzhen Li and Ozlem Altay and Elif Demirtas and Peltek, {Ibrahim Batuhan} and Burge Ulukan and Buket Yigit and Tarik Sipahioglu and {\'A}lvez, {Mar{\'i}a Bueno} and Lingqi Meng and Bayram Y{\"u}ksel and Hasan Turkez and Hale Kirimlioglu and Burcu Saka and Cihan Yurdaydin and Murat Akyildiz and Murat Dayangac and Mathias Uhlen and Jan Boren and Cheng Zhang and Adil Mardinoglu and Mujdat Zeybel",

note = "Publisher Copyright: {\textcopyright} 2025 The Authors",

year = "2025",

month = feb,

day = "18",

doi = "10.1016/j.xcrm.2025.101935",

language = "English",

volume = "6",

journal = "Cell Reports Medicine",

issn = "2666-3791",

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Yang, H, Atak, D, Yuan, M, Li, M, Altay, O, Demirtas, E, Peltek, IB, Ulukan, B, Yigit, B, Sipahioglu, T, Álvez, MB, Meng, L, Yüksel, B, Turkez, H, Kirimlioglu, H, Saka, B, Yurdaydin, C, Akyildiz, M, Dayangac, M, Uhlen, M, Boren, J, Zhang, C , Mardinoglu, A & Zeybel, M 2025, 'Integrative proteo-transcriptomic characterization of advanced fibrosis in chronic liver disease across etiologies', Cell Reports Medicine, vol. 6, no. 2, 101935. https://doi.org/10.1016/j.xcrm.2025.101935

TY - JOUR

T1 - Integrative proteo-transcriptomic characterization of advanced fibrosis in chronic liver disease across etiologies

AU - Yang, Hong

AU - Atak, Dila

AU - Yuan, Meng

AU - Li, Mengzhen

AU - Altay, Ozlem

AU - Demirtas, Elif

AU - Peltek, Ibrahim Batuhan

AU - Ulukan, Burge

AU - Yigit, Buket

AU - Sipahioglu, Tarik

AU - Álvez, María Bueno

AU - Meng, Lingqi

AU - Yüksel, Bayram

AU - Turkez, Hasan

AU - Kirimlioglu, Hale

AU - Saka, Burcu

AU - Yurdaydin, Cihan

AU - Akyildiz, Murat

AU - Dayangac, Murat

AU - Uhlen, Mathias

AU - Boren, Jan

AU - Zhang, Cheng

AU - Mardinoglu, Adil

AU - Zeybel, Mujdat

PY - 2025/2/18

Y1 - 2025/2/18

N2 - Chronic hepatic injury and inflammation from various causes can lead to fibrosis and cirrhosis, potentially predisposing to hepatocellular carcinoma. The molecular mechanisms underlying fibrosis and its progression remain incompletely understood. Using a proteo-transcriptomics approach, we analyze liver and plasma samples from 330 individuals, including 40 healthy individuals and 290 patients with histologically characterized fibrosis due to chronic viral infection, alcohol consumption, or metabolic dysfunction-associated steatotic liver disease. Our findings reveal dysregulated pathways related to extracellular matrix, immune response, inflammation, and metabolism in advanced fibrosis. We also identify 132 circulating proteins associated with advanced fibrosis, with neurofascin and growth differentiation factor 15 demonstrating superior predictive performance for advanced fibrosis(area under the receiver operating characteristic curve [AUROC] 0.89 [95% confidence interval (CI) 0.81–0.97]) compared to the fibrosis-4 model (AUROC 0.85 [95% CI 0.78–0.93]). These findings provide insights into fibrosis pathogenesis and highlight the potential for more accurate non-invasive diagnosis.

AB - Chronic hepatic injury and inflammation from various causes can lead to fibrosis and cirrhosis, potentially predisposing to hepatocellular carcinoma. The molecular mechanisms underlying fibrosis and its progression remain incompletely understood. Using a proteo-transcriptomics approach, we analyze liver and plasma samples from 330 individuals, including 40 healthy individuals and 290 patients with histologically characterized fibrosis due to chronic viral infection, alcohol consumption, or metabolic dysfunction-associated steatotic liver disease. Our findings reveal dysregulated pathways related to extracellular matrix, immune response, inflammation, and metabolism in advanced fibrosis. We also identify 132 circulating proteins associated with advanced fibrosis, with neurofascin and growth differentiation factor 15 demonstrating superior predictive performance for advanced fibrosis(area under the receiver operating characteristic curve [AUROC] 0.89 [95% confidence interval (CI) 0.81–0.97]) compared to the fibrosis-4 model (AUROC 0.85 [95% CI 0.78–0.93]). These findings provide insights into fibrosis pathogenesis and highlight the potential for more accurate non-invasive diagnosis.

KW - chronic liver disease

KW - liver fibrosis

KW - multi-omics

KW - non-invasive

KW - systems biology

UR - http://www.scopus.com/inward/record.url?scp=85217935601&partnerID=8YFLogxK

U2 - 10.1016/j.xcrm.2025.101935

DO - 10.1016/j.xcrm.2025.101935

M3 - Article

C2 - 39889710

AN - SCOPUS:85217935601

SN - 2666-3791

VL - 6

JO - Cell Reports Medicine

JF - Cell Reports Medicine

IS - 2

M1 - 101935

ER -

Integrative proteo-transcriptomic characterization of advanced fibrosis in chronic liver disease across etiologies

Abstract

Keywords

UN SDGs

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