Multi-omics profiling reveals CKM syndrome severity as a gradient risk factor for cancer: A prospective cohort study

IF 16.7 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental Pub Date : 2026-04-01 Epub Date: 2026-01-14 DOI:10.1016/j.metabol.2026.156508

Yu Huang , Yiwei Zhang , Yanjun Zhang , Ziliang Ye , Sisi Yang , Xiaoqin Gan , Yiting Wu , Yuanyuan Zhang , Xianhui Qin

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引用次数: 0

Abstract

Objective

Cardiovascular-Kidney-Metabolic (CKM) syndrome, a multisystem disorder, has been linked to cardiovascular and metabolic morbidity, but its association with cancer risk remains poorly characterized. This study aimed to examine the relationship between CKM syndrome severity and the incidence of overall cancer and 18 site-specific cancers, and to identify potential mediating plasma protein and metabolite signatures.

Methods

We analyzed data from 351,239 participants in the UK Biobank, classified into five CKM syndrome stages (0–4). Plasma proteomic (2923 proteins) and metabolomic (168 metabolites) profiles were analyzed. Cox models evaluated associations, and mediation analyses identified biological mediators.

Results

Over a median 13.5-year follow-up, 44,840 incident cancer cases were documented. Advancing CKM stages (0–3) showed a dose-response relationship with increased overall (per one-stage increase: adjusted HR, 1.05; 95%CI, 1.03–1.07) and eleven site-specific cancer risks (e.g., digestive, respiratory, urinary tracts) (per one-stage increase: adjusted HR ranging from 1.06 to 1.46). Stage 4 remained associated with elevated risk, though attenuated versus stage 3. Multi-omics mediation analysis identified 22 proteins and 2 metabolites that partially mediated the association between CKM stages 0–3 and overall cancer risk, implicating immune and metabolic pathways. Functional enrichment analysis further highlighted the PI3K-Akt signaling pathway and inflammatory processes as key mechanistic contributors.

Conclusions

CKM syndrome severity is independently associated with increased cancer risk, partially mediated by proteins and metabolites involved in inflammation, proliferation, and lipid metabolism. These findings support CKM staging as a multisystem disorder with significant oncological implications and highlight potential biomarkers for intervention.

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多组学分析显示CKM综合征严重程度是癌症的梯度危险因素：一项前瞻性队列研究。

目的：心血管-肾-代谢综合征（CKM）是一种多系统疾病，与心血管和代谢疾病有关，但其与癌症风险的关系尚不清楚。本研究旨在探讨CKM综合征严重程度与整体癌症和18种部位特异性癌症发病率之间的关系，并确定潜在的介导血浆蛋白和代谢物特征。方法：我们分析了英国生物银行351,239名参与者的数据，将其分为5个CKM综合征阶段（0-4）。分析血浆蛋白质组学（2923种蛋白质）和代谢组学（168种代谢物）谱。Cox模型评估了关联，中介分析确定了生物中介。结果：在中位13.5年的随访中，记录了44,840例癌症病例。CKM分期（0-3）的推进与总体（每一期增加：调整后的风险比为1.05；95%CI为1.03-1.07）和11个部位特异性癌症风险（如消化、呼吸、泌尿道）（每一期增加：调整后的风险比为1.06 - 1.46）的增加呈剂量反应关系。第4期与第3期相比风险有所降低，但仍与风险升高相关。多组学中介分析确定了22种蛋白质和2种代谢物，这些蛋白质和代谢物部分介导了CKM 0-3期与总体癌症风险之间的关联，涉及免疫和代谢途径。功能富集分析进一步强调PI3K-Akt信号通路和炎症过程是关键的机制因素。结论：CKM综合征严重程度与癌症风险增加独立相关，部分由参与炎症、增殖和脂质代谢的蛋白质和代谢物介导。这些发现支持CKM分期是一种多系统疾病，具有重要的肿瘤学意义，并强调了干预的潜在生物标志物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Metabolism: clinical and experimental 医学-内分泌学与代谢

CiteScore

18.90

自引率

3.10%

发文量

310

审稿时长

16 days

期刊介绍： Metabolism upholds research excellence by disseminating high-quality original research, reviews, editorials, and commentaries covering all facets of human metabolism. Consideration for publication in Metabolism extends to studies in humans, animal, and cellular models, with a particular emphasis on work demonstrating strong translational potential. The journal addresses a range of topics, including: - Energy Expenditure and Obesity - Metabolic Syndrome, Prediabetes, and Diabetes - Nutrition, Exercise, and the Environment - Genetics and Genomics, Proteomics, and Metabolomics - Carbohydrate, Lipid, and Protein Metabolism - Endocrinology and Hypertension - Mineral and Bone Metabolism - Cardiovascular Diseases and Malignancies - Inflammation in metabolism and immunometabolism