(1) Background: The incidence of hepatocellular carcinoma (HCC) is rising, and current screening methods lack sensitivity. This study aimed to identify distinct and overlapping metabolites in saliva and plasma that are significantly associated with HCC. (2) Methods: Saliva samples were collected from 42 individuals (HCC = 16, cirrhosis = 12, healthy = 14), with plasma samples from 22 (HCC = 14, cirrhosis = 2, healthy = 6). We performed untargeted mass spectrometry on blood and plasma, tested metabolites for associations with HCC or cirrhosis using a logistic regression, and identified enriched pathways with Metaboanalyst. Pearson’s correlation was employed to test for correlations between salivary and plasma metabolites. (3) Results: Six salivary metabolites (1-hexadecanol, isooctanol, malonic acid, N-acetyl-valine, octadecanol, and succinic acid) and ten plasma metabolites (glycine, 3-(4-hydroxyphenyl)propionic acid, aconitic acid, isocitric acid, tagatose, cellobiose, fucose, glyceric acid, isocitric acid, isothreonic acid, and phenylacetic acid) were associated with HCC. Malonic acid was correlated between the paired saliva and plasma samples. Pathway analysis highlighted deregulation of the ‘The Citric Acid Cycle’ in both biospecimens. (4) Conclusions: Our study suggests that salivary and plasma metabolites may serve as independent sources for HCC detection. Despite the lack of correlation between individual metabolites, they converge on ‘The Citric Acid Cycle’ pathway, implicated in HCC pathogenesis.
（1）背景：肝细胞癌（HCC）发病率持续上升，现有筛查方法敏感性不足。本研究旨在鉴定唾液与血浆中与HCC显著相关的特异性及重叠性代谢物。（2）方法：收集42例受试者（HCC=16例、肝硬化=12例、健康=14例）唾液样本及其中22例（HCC=14例、肝硬化=2例、健康=6例）血浆样本。采用非靶向质谱技术分析血液与血浆样本，通过逻辑回归检验代谢物与HCC或肝硬化的关联性，并利用Metaboanalyst进行通路富集分析。采用皮尔逊相关检验分析唾液与血浆代谢物的相关性。（3）结果：六种唾液代谢物（1-十六烷醇、异辛醇、丙二酸、N-乙酰缬氨酸、十八烷醇、琥珀酸）及十种血浆代谢物（甘氨酸、3-(4-羟基苯基)丙酸、乌头酸、异柠檬酸、塔格糖、纤维二糖、岩藻糖、甘油酸、异柠檬酸、异苏糖酸、苯乙酸）与HCC相关。配对唾液与血浆样本中丙二酸呈显著相关性。通路分析揭示两种生物样本中均存在“三羧酸循环”通路失调。（4）结论：本研究提示唾液与血浆代谢物可作为HCC检测的独立生物标志物来源。尽管个体代谢物间缺乏强相关性，但其共同指向与HCC发病机制相关的“三羧酸循环”通路。
Characterization of Salivary and Plasma Metabolites as Biomarkers for HCC: A Pilot Study
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