癌症恶病质（CCx）提出了多方面的挑战，其特征是负蛋白质和能量平衡以及全身炎症反应激活。虽然之前的 CCx 研究主要集中在小鼠模型或人体体液上，但阐明人类 CCx 病理生理学背后的分子器官间串扰的需求尚未得到满足。空间代谢组学对肝脏、骨骼肌、皮下和内脏脂肪组织进行了研究，以及来自恶病质和对照癌症患者的血清。使用成分、通路富集和相关网络分析进行器官方面的比较。使用 Circos 评估 CCx 改变途径的器官间相关性。对组织和血清的机器学习建立了分类器作为 CCx 的潜在诊断生物标志物。在 CCx 中检测到明显的代谢途径改变，其中脂肪组织和肝脏表现出最显着的代谢紊乱 (P ≤ 0.05)。与对照患者相比，CCx 患者的内脏和皮下脂肪组织以及肝脏的代谢活动增加，而肌肉和血清的代谢活动减少。碳水化合物、脂质、氨基酸和维生素代谢在 CCx 中作为跨不同器官系统的高度相互作用的途径出现。 CCx 患者的肌肉组织能量电荷减少 (P ≤ 0.001)，而肝脏和脂肪组织能量电荷增加 (P ≤ 0.001)。我们根据严重程度和代谢变化对 CCx 患者进行分层，发现内脏脂肪组织受影响最大，尤其是在严重恶病质的情况下。形态分析显示内脏脂肪组织中的脂肪细胞尺寸较小（P≤0.05），表明分解代谢过程。我们开发了针对特定器官的癌症恶病质的基于组织的分类器，促进患者血清作为器官构成中 CCx 的微创诊断标记物的转移。这些发现支持 CCx 作为具有多种代谢的多器官综合征的概念。改变，提供对人类 CCx 的病理生理学和器官串扰的见解。这项研究开创了 CCx 的空间代谢组学，证明了使用血清在器官水平区分恶病质状态的可行性。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

Cancer cachexia (CCx) presents a multifaceted challenge characterized by negative protein and energy balance and systemic inflammatory response activation. While previous CCx studies predominantly focused on mouse models or human body fluids, there's an unmet need to elucidate the molecular inter-organ cross-talk underlying the pathophysiology of human CCx.Spatial metabolomics were conducted on liver, skeletal muscle, subcutaneous and visceral adipose tissue, and serum from cachectic and control cancer patients. Organ-wise comparisons were performed using component, pathway enrichment and correlation network analyses. Inter-organ correlations in CCx altered pathways were assessed using Circos. Machine learning on tissues and serum established classifiers as potential diagnostic biomarkers for CCx.Distinct metabolic pathway alteration was detected in CCx, with adipose tissues and liver displaying the most significant (P ≤ 0.05) metabolic disturbances. CCx patients exhibited increased metabolic activity in visceral and subcutaneous adipose tissues and liver, contrasting with decreased activity in muscle and serum compared to control patients. Carbohydrate, lipid, amino acid, and vitamin metabolism emerged as highly interacting pathways across different organ systems in CCx. Muscle tissue showed decreased (P ≤ 0.001) energy charge in CCx patients, while liver and adipose tissues displayed increased energy charge (P ≤ 0.001). We stratified CCx patients by severity and metabolic changes, finding that visceral adipose tissue is most affected, especially in cases of severe cachexia. Morphometric analysis showed smaller (P ≤ 0.05) adipocyte size in visceral adipose tissue, indicating catabolic processes. We developed tissue-based classifiers for cancer cachexia specific to individual organs, facilitating the transfer of patient serum as minimally invasive diagnostic markers of CCx in the constitution of the organs.These findings support the concept of CCx as a multi-organ syndrome with diverse metabolic alterations, providing insights into the pathophysiology and organ cross-talk of human CCx. This study pioneers spatial metabolomics for CCx, demonstrating the feasibility of distinguishing cachexia status at the organ level using serum.Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.