Comprehensive Metabolomic Profiling Delineates Stage-Specific Lipid-Centric Remodeling in Cardiovascular-Kidney-Metabolic Syndrome

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Abstract Title *

Comprehensive Metabolomic Profiling Delineates Stage-Specific Lipid-Centric Remodeling in Cardiovascular-Kidney-Metabolic Syndrome

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Co-author 1

Xuemei Gong gxm4171211@163.com West China Hospital of Sichuan University Department of Nephrology,Institute of Kidney Diseases Chengdu China *

Co-author 2

Chunyang Li lichunyang@wchscu.edu.cn West China Hospital of Sichuan University West China Biomedical Big Data Center Chengdu China -

Co-author 3

Jing Chen chenj397@mail2.sysu.edu.cn Affiliated Hospital of Zunyi Medical University Department of Nephrology Zunyi China -

Co-author 4

Yujiao Wang wangyujiao9936@163.com West China Hospital of Sichuan University Department of Nephrology, Institute of Kidney Diseases Chengdu China -

Co-author 5

Wenge Tang 690615630@qq.com Chongqing Municipal Center for Disease Control and Prevention Chongqing Municipal Center for Disease Control and Prevention Chongqing China -

Co-author 6

Xuehui Zhang zhangxuehui1015@126.com School of Public Health Kunming Medical University Kunming China -

Co-author 7

Jianzhong Yin yinjianzhong2005@sina.com Kunming Medical University School of Public Health Kunming China -

Co-author 8

Xing Zhao xingzhao@scu.edu.cn Sichuan University West China School of Public Health and West China Fourth Hospital Chengdu China -

Co-author 9

Haopeng Yu yuhaopeng@wchscu.edu.cn West China Hospital of Sichuan University West China Biomedical Big Data Center Chengdu China -

Co-author 10

Ping Fu fupinghx@scu.edu.cn West China Hospital of Sichuan University Department of Nephrology, Institute of Kidney Diseases Chengdu China -

Co-author 11

Xiaoxi Zeng zengxiaoxi@wchscu.edu.cn West China Hospital of Sichuan University Department of Nephrology, Institute of Kidney Diseases Chengdu China -

Co-author 12

Co-author 13

Co-author 14

Co-author 15

Introduction

Progression of Cardiovascular–Kidney–Metabolic (CKM) syndrome involves escalating metabolic dysfunction, yet the underlying molecular remodeling remains unclear. This study aims to delineate comprehensive metabolic landscape across CKM stages and identify robust biomarkers for advanced CKM.

Methods

Using the China Multi-Ethnic Cohort (CMEC), we analyzed plasma metabolomic profiles from 1,374 Chinese participants with CKM stages 0–4. Untargeted metabolomics using liquid chromatography–mass spectrometry (LC–MS) quantified 1,427 metabolites, followed by differential analysis and weighted gene co-expression network analysis (WGCNA) to identify key differential metabolites. Functional enrichment analysis was further conducted to reveal alterations in significant metabolic pathways, and machine learning was employed to evaluate the potential of metabolites as biomarkers for advanced stages.

Results

Metabolomic profiles exhibited progressive metabolic remodeling across CKM stages, with minimal changes in early stages (1–2) but marked separation in advanced stages (3–4). Differential analysis identified a total of 148 metabolites were significantly dysregulated during CKM syndrome progression, the majority of which were fatty acyls, steroids, and steroid derivatives. And specific lipid-centric pathways, notably steroid derivatives -related metabolic pathways and neuroactive ligand-receptor interactions, as key dysregulated pathways. WGCNA identified a blue module (324 metabolites) strongly associated with CKM progression, overlapping 38 metabolites with differential analysis. Integrating these 38 metabolites with clinical variables significantly improved diagnostic performance for detecting advanced CKM (AUPRC 0.78, 0.67-0.87) compared to clinical factors alone (AUPRC 0.74, 0.62-0.84).

Conclusion

Comprehensive metabolomic profiling delineates stage-specific metabolic remodeling in CKM syndrome and identifies lipid-centric pathways central to disease progression. Integrating metabolites signatures with clinical variables enhances diagnostic performance for advanced stages, offering a promising strategy for early risk stratification and precision intervention in high-risk populations.

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