华氏堡效应是癌细胞更倾向于使用糖酵解而不是氧化磷酸化来产生能量的特点。越来越多的证据表明，有氧糖酵解在肝细胞癌（HCC）中普遍存在，并与肿瘤发生密切相关。本研究的目的是探讨Forkhead Box P2 (FOXP2) 在HCC的有氧糖酵解和肿瘤发生中的作用和机制。我们发现 FOXP2 在HCC组织和细胞中的表达较非肿瘤组织和正常肝细胞低。FOXP2 的过表达抑制了体外HCC细胞的增殖和侵袭，促进了细胞凋亡，并抑制了小鼠异种移植瘤的生长。进一步的研究表明，FOXP2 抑制了HCC细胞的华氏堡效应。此外，我们证明了FOXP2 上调果糖-1，6-二磷酸酶（FBP1）的表达，而FOXP2 对糖酵解的抑制作用依赖于FBP1。在机制上，作为转录因子，FOXP2 负调控了赖氨酸特异性去甲基化酶5A（KDM5A）的转录，并阻断了KDM5A 引起的FBP1启动子区域H3K4me3去甲基化，从而促进了FBP1的表达。一致地，过表达KDM5A或沉默FBP1有效地逆转了FOXP2 对HCC进展的抑制作用。综上所述，我们的研究发现了FOXP2/KDM5A/FBP1轴在HCC细胞的糖酵解和恶性进展中的机制作用，为HCC治疗提供了潜在的分子靶点。© 2023 Wiley Periodicals LLC.

The Warburg effect is the preference of cancer cells to use glycolysis rather than oxidative phosphorylation to generate energy. Accumulating evidence suggests that aerobic glycolysis is widespread in hepatocellular carcinoma (HCC) and closely related to tumorigenesis. The purpose of this study was to investigate the role and mechanism of forkhead box P2 (FOXP2) in aerobic glycolysis and tumorigenesis in HCC. Here, we found that FOXP2 was lower expressed in HCC tissues and cells than in nontumor tissues and normal hepatocytes. Overexpression of FOXP2 suppressed cell proliferation and invasion of HCC cells and promoted cell apoptosis in vitro, and hindered the growth of mouse xenograft tumors in vivo. Further researches showed that FOXP2 inhibited the Warburg effect in HCC cells. Moreover, we demonstrated that FOXP2 up-regulated the expression of fructose-1, 6-diphosphatase (FBP1), and the inhibitory effect of FOXP2 on glycolysis was dependent on FBP1. Mechanistically, as a transcription factor, FOXP2 negatively regulated the transcription of lysine-specific demethylase 5A (KDM5A), and then blocked KDM5A-induced H3K4me3 demethylation in FBP1 promoter region, thereby promoting the expression of FBP1. Consistently, overexpressing KDM5A or silencing FBP1 effectively reversed the inhibitory effect of FOXP2 on HCC progression. Together, our findings revealed the mechanistic role of the FOXP2/KDM5A/FBP1 axis in glycolysis and malignant progression of HCC cells, providing a potential molecular target for the therapy of HCC.© 2023 Wiley Periodicals LLC.