Classon Peyton, Wixom Alexander Q, Calixto Mancipe Natalia, Graham Rondell P, Zhao Yu, Tran Nguyen, Taner Timucin, Povero Davide
Department of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street, Rochester, MN 55905, USA.
Department of Quantitative Health Sciences, Division of Computational Biology, Mayo Clinic, 200 First Street, Rochester, MN 55905, USA.
Am J Physiol Gastrointest Liver Physiol. 2025 Aug 28. doi: 10.1152/ajpgi.00096.2025.
Metabolic-associated steatohepatitis-driven hepatocellular carcinoma (MASH-HCC) incidence is rapidly rising worldwide. Lipid metabolic reprogramming is a hallmark of solid tumors to satisfy cancer high metabolic demand. However, it may confer sensitivity to ferroptosis, a cell death mode driven by iron-dependent lipid peroxidation. In this report, we describe the lipid metabolic landscape in MASH-HCC and characterize long chain acyl-CoA synthetases (ACSLs), a family of enzymes involved in synthesis of cellular lipids. Bulk RNA-sequencing, single-cell RNA-sequencing, spatial transcriptomics and immunohistochemistry analyses of human MASH-HCC were integrated to identify differentially expressed lipid metabolism genes. Ferroptosis was assessed in human HCC cell lines. A characterization of ACSLs was also conducted at the single-cell level in a diet-induced experimental murine model of MASH-HCC. Our analysis revealed that in human MASH-HCC, ACSLs exhibit a heterogeneous expression, with ACSL4 notably enriched in tumor tissues, contrasting with ACSL5 upregulation in non-cancerous MASH. We identified a unique lipid metabolic gene signature of MASH-HCC, which included genes associated with ferroptosis vulnerability. , high ACSL4 expression was associated with increased ferroptosis sensitivity in human HCC cell lines. Lastly, single-cell RNA-sequencing revealed elevated ACSL4 expression in immune cells in a murine MASH-HCC model, suggesting a role of ACSL4 in shaping the tumor immune microenvironment. Overall, this report offers new insights into lipid metabolic landscape and ferroptosis sensitivity for novel MASH-HCC treatments.
代谢相关脂肪性肝炎驱动的肝细胞癌（MASH-HCC）的发病率在全球范围内正在迅速上升。脂质代谢重编程是实体瘤的一个标志，以满足癌症对高代谢的需求。然而，它可能使细胞对铁死亡敏感，铁死亡是一种由铁依赖性脂质过氧化驱动的细胞死亡模式。在本报告中，我们描述了MASH-HCC中的脂质代谢格局，并对长链酰基辅酶A合成酶（ACSLs）进行了表征，ACSLs是一类参与细胞脂质合成的酶。我们整合了对人类MASH-HCC的批量RNA测序、单细胞RNA测序、空间转录组学和免疫组织化学分析，以鉴定差异表达的脂质代谢基因。在人类肝癌细胞系中评估了铁死亡情况。我们还在饮食诱导的MASH-HCC实验小鼠模型中，在单细胞水平上对ACSLs进行了表征。我们的分析表明，在人类MASH-HCC中，ACSLs表现出异质性表达，ACSL4在肿瘤组织中显著富集，这与非癌性MASH中ACSL5的上调形成对比。我们确定了MASH-HCC独特的脂质代谢基因特征，其中包括与铁死亡易感性相关的基因。在人类肝癌细胞系中，ACSL4的高表达与铁死亡敏感性增加有关。最后，单细胞RNA测序显示免疫细胞中ACSL4在小鼠MASH-HCC模型中表达升高，这表明ACSL4在塑造肿瘤免疫微环境中发挥作用。总体而言，本报告为新型MASH-HCC治疗的脂质代谢格局和铁死亡敏感性提供了新的见解。
