分子分类是肝细胞癌（HCC）预后预测和优化精准治疗的有希望的工具。因此，我们旨在基于脂肪酸降解（FAD）途径开发一种分子分类，并对其进行全面的特征化，并评估其在指导个体化治疗方面的能力。我们对41名HCC患者进行了RNA测序（RNA-seq）、PCR阵列、脂质组学、代谢组学和蛋白质组学分析，其中17名患者接受了抗PD-1治疗。我们进行了单细胞RNA测序（scRNA-seq）以探索肿瘤微环境。我们分析了近60个公开可用的多组学数据集。我们评估了FAD亚型与索拉非尼、经动脉化疗栓塞（TACE）、免疫检查点抑制剂（ICI）治疗的关联，在患者群、患者源性异种移植模型（PDX）和自发性小鼠模型中进行了评估。我们基于FAD途径确定了一个名为F亚型（F1、F2和F3）的新的分子分类，根据临床，突变，表观遗传，代谢和免疫特性进行划分。F1亚型表现出高度浸润性的免疫抑制性微环境。我们确定了亚型特异性的治疗策略，其中F1亚型具有最低的FAD活性，对YM-155和Alisertib化合物，索拉非尼，抗PD1，抗PD-L1以及关联的泊珠单抗（T + A）治疗具有响应性，而F3亚型具有最高的FAD活性，对TACE具有响应性。F2亚型处于F1和F3之间的中间状态，可能对T + A联合治疗有响应性。我们提供了FAD亚型可以基于液态活检进行诊断的初步证据。我们确定了三个具有独特临床和生物学特征的FAD亚型，这可以优化个体化的癌症患者治疗并帮助临床决策。版权所有©2023作者。由Wolters Kluwer Health, Inc.出版。

Molecular classification is a promising tool for prognosis prediction and optimizing precision therapy for hepatocellular carcinoma (HCC). Here, we aimed to develop a molecular classification of HCC based on the fatty acid degradation (FAD) pathway, fully characterize it, and evaluate its ability in guiding personalized therapy.We performed RNA sequencing (RNA-seq), PCR-array, lipidomics, metabolomics, and proteomics analysis of 41 HCC patients, in which 17 patients received anti-PD-1 therapy. Single-cell RNA sequencing (scRNA-seq) was performed to explore the tumor microenvironment. Nearly 60 publicly-available multi-omics datasets were analyzed. The associations between FAD subtypes and response to sorafenib, transarterial chemoembolization (TACE), immune checkpoint inhibitor (ICI) were assessed in patient cohorts, patient-derived xenograft (PDX), and spontaneous mice models. A novel molecular classification named F subtype (F1, F2, and F3) was identified based on the FAD pathway, distinguished by clinical, mutational, epigenetic, metabolic, and immunological characteristics. F1 subtypes exhibited high infiltration with immunosuppressive microenvironment. Subtype-specific therapeutic strategies were identified, in which F1 subtypes with the lowest FAD activities represent responders to compounds YM-155 and Alisertib, sorafenib, anti-PD1, anti-PD-L1, and atezolizumab plus bevacizumab (T + A) treatment, while F3 subtypes with the highest FAD activities are responders to TACE. F2 subtypes, the intermediate status between F1 and F3, are potential responders to T + A combinations. We provide preliminary evidence that the FAD subtypes can be diagnosed based on liquid biopsies.We identified three FAD subtypes with unique clinical and biological characteristics, which could optimize individual cancer patient therapy and help clinical decision-making.Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.