Novel biomarkers for HCC surveillance in cirrhotic patients are urgently needed. Exosomes and their lipid content in particular represent potentially valuable noninvasive diagnostic biomarkers. We isolated exosomes from plasma of 72 cirrhotic patients, including 31 with HCC. Exosomes and unfractionated plasma were processed for untargeted lipidomics using ultra–high-resolution mass spectrometry. A total of 2,864 lipid species, belonging to 52 classes, were identified. Both exosome fractionation and HCC diagnosis had significant impact on the lipid profiles. Ten lipid classes were enriched in HCC exosomes compared with non-HCC exosomes. Dilysocardiolipins were detected in 35% of the HCC exosomes but in none of the non-HCC exosomes ( P < 0.001). Cardiolipins and sphingosines had the highest differential effects (fold change of 133.08, q = 0.001 and 38.57, q < 0.001, respectively). In logistic regression analysis, high abundances of exosomal sphingosines, dilysocardiolipins, lysophosphatidylserines, and (O-acyl)-1-hydroxy fatty acids were strongly associated with HCC [OR (95% confidence interval (CI)), 271.1 (14.0–5,251.9), P < 0.001; 46.5 (2.3–939.9), P = 0.012; 14.9 (4.3–51.2), P < 0.001; 10.3 (3.2–33.1), P < 0.001]. Four lipid classes were depleted in HCC exosomes compared with non-HCC exosomes. In logistic regression analysis, lack of detection of sulfatides and acylGlcSitosterol esters was strongly associated with HCC [OR (95% CI): 215.5 (11.5–4,035.9), P < 0.001; 26.7 (1.4–528.4), P = 0.031]. These HCC-associated changes in lipid composition of exosomes reflected alterations in glycerophospholipid metabolism, retrograde endocannabinoid signaling, and ferroptosis. In conclusion, this study identified candidate biomarkers for early detection of HCC as well as altered pathways in exosomes that may contribute to tumor development and progression. Prevention Relevance: This study identifies lipids in circulating exosomes, that could serve as biomarkers for the early detection of hepatocellular carcinoma as well as altered pathways in exosomes that may contribute to tumor development and progression.

中文翻译：

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血浆外泌体的脂质组学特征确定了早期检测肝硬化患者肝细胞癌的候选生物标志物

迫切需要用于肝硬化患者 HCC 监测的新型生物标志物。外泌体及其脂质含量尤其代表了潜在的有价值的非侵入性诊断生物标志物。我们从 72 名肝硬化患者的血浆中分离出外泌体，其中 31 名患有 HCC。使用超高分辨率质谱法处理外泌体和未分级血浆用于非靶向脂质组学。共鉴定出属于 52 类的 2,864 种脂质。外泌体分级分离和 HCC 诊断都对脂质谱有显着影响。与非 HCC 外泌体相比，HCC 外泌体中富集了 10 个脂质类别。在 35% 的 HCC 外泌体中检测到二溶心磷脂，但在非 HCC 外泌体中均未检测到（P < 0.001）。心磷脂和鞘氨醇具有最高的差异效应（倍数变化为 133.08，q = 0。001 和 38.57，q < 0.001，分别）。在逻辑回归分析中，高丰度的外泌体鞘氨醇、二溶血磷脂、溶血磷脂酰丝氨酸和（O-酰基）-1-羟基脂肪酸与 HCC 密切相关 [OR（95% 置信区间 (CI)），271.1 (14.0–5,251.9) , P < 0.001; 46.5 (2.3–939.9)，P = 0.012；14.9 (4.3–51.2), P < 0.001; 10.3 (3.2–33.1), P < 0.001]。与非 HCC 外泌体相比，HCC 外泌体中耗尽了四种脂质类别。在逻辑回归分析中，未检测到硫苷脂和酰基谷甾醇酯与 HCC 密切相关 [OR (95% CI)：215.5 (11.5–4,035.9)，P < 0.001；26.7 (1.4–528.4)，P = 0.031]。这些与 HCC 相关的外泌体脂质组成变化反映了甘油磷脂代谢、逆行内源性大麻素信号传导和铁死亡的变化。总之，本研究确定了用于早期检测 HCC 的候选生物标志物以及可能有助于肿瘤发展和进展的外泌体中改变的途径。预防相关性：本研究确定了循环外泌体中的脂质，这些脂质可以作为早期检测肝细胞癌的生物标志物，以及可能有助于肿瘤发展和进展的外泌体中改变的通路。