Your new experience awaits. Try the new design now and help us make it even better

ORIGINAL RESEARCH article

Front. Endocrinol.

Sec. Systems Endocrinology

Volume 16 - 2025 | doi: 10.3389/fendo.2025.1664691

A proteome-wide association study reveals novel plasma proteins as potential therapeutic targets for metabolic dysfunction-associated steatotic liver disease

Provisionally accepted
Nanwei  TongNanwei Tong1*Qian  ZhongQian Zhong1Yue  ZhuYue Zhu1Yiwen  TanYiwen Tan2Wenzeng  DengWenzeng Deng3Chunxia  WangChunxia Wang2Shan  YangShan Yang2
  • 1West China Hospital, Sichuan University, Chengdu, China
  • 2The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
  • 3Chongqing University Qianjiang Hospital, Chongqing, China

The final, formatted version of the article will be published soon.

Introduction: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global health burden with limited therapeutic options. To identify novel proteins involved in its pathogenesis and reveal potential drug targets, we performed an integrative analysis combining plasma proteomic data with genome-wide association study (GWAS) summary statistics for MASLD. Methods: A proteome-wide association study (PWAS) was conducted by integrating plasma protein quantitative trait loci (pQTL) data with GWAS summary statistics from the FinnGen R11 MASLD cohort (used as the discovery dataset) and a large-scale MASLD GWAS meta-analysis (used for validation). Causal inference was assessed using Mendelian Randomization (MR), and Bayesian colocalization was applied to identify shared genetic signals. Additionally, liver specimens from five healthy controls and five MASLD patients were subjected to H&E and NCAN immunohistochemistry. Results: PWAS in the discovery cohort identified three plasma proteins—NCAN, EPHA2, and APOE— significantly associated with MASLD risk. Among them, NCAN showed the strongest and most consistent association, which was replicated in the validation cohort. MR analyses supported a causal role for NCAN in both cohorts, whereas colocalization at the NCAN locus was suggestive rather than definitive. and colocalization analysis revealed a shared causal variant at the NCAN locus (posterior probability for colocalization [PP4 + PP3] ≥ 0.8). Immunohistochemical analysis showed that NCAN expression was significantly reduced in MASLD liver tissues. Conclusions: This integrative proteomic and genetic study identified NCAN as a key contributor to MASLD pathogenesis. Its consistent association and genetic evidence across two independent cohorts highlight NCAN as a promising therapeutic target that merits further functional investigation.

Keywords: MASLD, Proteome-wide association study, Mendelian randomization, NCAN, Liver Diseases, Genetics

Received: 12 Jul 2025; Accepted: 03 Oct 2025.

Copyright: © 2025 Tong, Zhong, Zhu, Tan, Deng, Wang and Yang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Nanwei Tong, tongnw@scu.edu.cn

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.