肝细胞癌（HCC）是全球癌症死亡的主要原因之一，但早期诊断生物标志物和治疗靶点不足。药物耐药占据了大多数HCC相关死亡原因，但其机制仍不清楚。RNA测序鉴定了肝癌干细胞（CSCs）中Frizzled-10（FZD10）的表达，并通过实时PCR和免疫组织化学予以验证。使用体外和体内实验评估了FZD10对肝CSCs扩展和lenvatinib耐受性的影响。RNA测序、RNA结合蛋白免疫沉淀和荧光素酶报告试验被用于探索FZD10介导的肝CSCs扩展和lenvatinib耐受性机制。FZD10在肝CSCs中的激活是通过METTL3依赖性的FZD10 mRNA的m6A甲基化介导的。功能研究表明，FZD10通过激活β-氨基酸和YAP1促进肝CSCs的自我更新、肿瘤形成和转移。FZD10-β-氨基酸/YAP1轴在肝CSCs中被激活并预示了不良预后。此外，FZD10-β-氨基酸-c-Jun轴通过转录激活METTL3表达，形成正反馈环路。重要的是，FZD10/β-氨基酸/c-Jun/MEK/ERK轴决定了肝细胞瘤对lenvatinib治疗的反应。对患者队列、患者来源的肿瘤器官结构（PDOs）和患者来源的异种移植瘤（PDXs）的分析进一步表明，FZD10可能预测HCC患者lenvatinib的临床效益。此外，使用目标FZD10的腺相关病毒（AAV）或β-氨基酸抑制剂治疗lenvatinib耐药性HCC恢复了其对lenvatinib的反应。高水平的FZD10表达促进了肝CSCs的扩展和lenvatinib耐药性，表明FZD10表达是人类HCC的一种新的预后生物标志物和治疗靶点。版权所有©2023 AGA学会，Elsevier Inc.发表。保留所有权利。

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide, but there is deficiency of early diagnosis biomarkers and therapeutic targets. Drug-resistance account for most HCC-related deaths, yet the mechanisms underlying drug-resistance remain poorly understood.The expression of Frizzled-10 (FZD10) in liver cancer stem cells (CSCs) was identified by RNA sequencing and validated by real-time PCR and immunohistochemistry. In vitro and in vivo experiments were used to assess the effect of FZD10 on liver CSCs expansion and lenvatinib resistance. RNA sequencing, RNA binding protein immunoprecipitation and luciferase report assays were applied to explore the mechanism underlying FZD10-mediated liver CSCs expansion and lenvatinib resistance.The activation of FZD10 in liver CSCs was mediated by METTL3-dependent m6A methylation of FZD10 mRNA. Functional studies revealed that FZD10 promotes liver CSCs self-renewal, tumorigenicity and metastasis via activating β-catenin and YAP1. The FZD10-β-catenin/YAP1 axis is activated in liver CSCs and predicts poor prognosis. Moreover, FZD10-β-catenin-c-Jun axis transcriptionally activates METTL3 expression, forming a positive feedback loop. Importantly, FZD10/β-catenin/c-Jun/MEK/ERK axis determines the responses of hepatoma cells to lenvatinib treatment. Analysis of patient cohort, patient-derived tumor organoids (PDOs) and patient-derived xenografts (PDXs) further suggest that FZD10 might predict lenvatinib clinical benefit in HCC patients. Furthermore, treatment of lenvatinib-resistant HCC with adeno-associated virus (AAV) targeting FZD10 or an β-catenin inhibitor restored lenvatinib response.Elevated FZD10 expression promotes liver CSCs expansion and lenvatinib resistance, indicating that FZD10 expression is a novel prognostic biomarker and therapeutic target for human HCC.Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.