组蛋白去乙酰化酶（histone deacetylase，HDAC）I类和IIa类在肝细胞癌（hepatocellular carcinoma，HCC）中高度表达，并与存活率降低有关。但是，临床使用的泛HDAC和I类抑制剂有严重的不良事件。在本研究中，我们评估了IIa类HDAC抑制剂（HDACI）与lenvatinib联合使用的抗肿瘤效果和耐受性，lenvatinib是治疗HCC的标准疗法。 IIa类HDACI与lenvatinib联合治疗在人类HCC细胞系中表现出协同的抗肿瘤效应。在小鼠模型中，该疗法显示了显著的抗肿瘤效果，并发生了少量不良事件。在免疫印迹中，纤维母细胞生长因子受体4（fibroblast growth factor receptor 4，FGFR4）和纤维母细胞生长因子19（fibroblast growth factor 19，FGF19）的表达在表现出高抗肿瘤效应的细胞系中很高。此外，IIa类HDACI的给药可以减少FGFR4的表达。在小分子干扰RNA（small interfering RNA，siRNA）分析中，HDAC9的沉默（HDAC I类的一种异构体）可以减少FGFR4的表达并诱导细胞凋亡。临床组织免疫组化显示，FGFR4在HCC中的阳性率为32％，HDAC9为84％，所有FGFR4阳性的患者均为HDAC9阳性。 IIa类HDACI和lenvatinib联合治疗通过下调FGFR4和阻断FGFR信号通路而诱导细胞凋亡，对FGFR4阳性的HCC细胞系表现出协同的抗肿瘤效应和安全性。这种联合治疗克服了传统治疗的问题，并将对FGFR4阳性的HCC患者有益。 ©2023亚太肝脏研究协会。

Histone deacetylase (HDAC) class I and IIa are highly expressed in hepatocellular carcinoma (HCC) and associated with decreased survival. However, clinically used pan and class I inhibitors have serious adverse events. In this study, we assessed the antitumor effects and tolerability of class IIa HDAC inhibitor (HDACI) with lenvatinib, which is a standard therapy for HCC.Combination therapy with class IIa HDACI and lenvatinib exerted synergistic antitumor effect in human HCC cell lines. In mouse models, this therapy showed significant antitumor effects, and few adverse events occurred. In immunoblotting, the expression of fibroblast growth factor receptor 4 (FGFR4) and fibroblast growth factor 19 (FGF19) was high in cell lines that showed a high antitumor effect. In addition, class IIa HDACI administration decreased the expression of FGFR4. In the small interfering RNA (siRNA) analysis, knockdown of HDAC9, which is an isoform of HDAC class IIa, reduced the expression of FGFR4 and induced apoptosis. Immunohistochemistry of human clinical specimens showed a positivity rate of 32% for FGFR4 and 84% for HDAC9 in HCC, and all FGFR4-positive patients were HDAC9 positive.Class IIa HDACI and lenvatinib combination therapy induces apoptosis by downregulating FGFR4 and blocking the FGFR signaling in FGFR4-positive HCC cell lines and has demonstrated synergistic antitumor effects and safety. This combination therapy overcomes the problems of conventional therapies and will be beneficial for FGFR4-positive HCC patients.© 2023. Asian Pacific Association for the Study of the Liver.