Hepatocyte nuclear factor 4-Alpha: a key regulator in liver carcinogenesis

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, associated with viral hepatitis, alcohol consumption, and non-alcoholic fatty liver disease. Hepatocyte nuclear factor 4 alpha (HNF4α), a crucial transcription factor for liver function (glucose and lipid metabolism, bile acid homeostasis, and cellular differentiation), is often dysregulated in HCC progression. This review provides a comprehensive overview of the role of HNF4α in hepatic oncogenesis, providing novel inshight into its regulatory effects on epithelial-mesenchymal transition (EMT), metabolic alterations (including the Warburg effect), cell cycle control, and tumor microenvironment. We also discuss therapeutic strategies targeting HNF4α focusing on restoring metabolic balance and inducing apoptosis. This integrated analysis advances our understanding of HNF4α's contribution to HCC and may pave the way for the development of targeted therapies (Fig. 1).

Keywords: Epithelial-mesenchymal transition; HNF4α; Hepatocellular carcinoma; Progression.

Fig. 1

Hepatocyte Nuclear Factor 4α (HNF4α) in Hepatocellular Carcinoma (HCC). Downregulation of HNF4α promotes HCC progression through Epithelial-Mesenchymal Transition (EMT), metabolic reprogramming, and immune dysregulation. Transcriptional control of HNF4α is impacted by Wilms Tumor 1 (WT1), tumor protein P53 (p53), mitogen-activated protein kinase (MAPK) signaling, lysine-specific demethylase 1 A (KDM1A), glycogen synthase kinase 3 beta (GSK-3β), and Yes-associated protein 1 (YAP1). Potential therapeutic strategies targeting HNF4α include small molecule activation and gene therapy. Created with BioRender (BioRender.com)

Fig. 2

HNF4α’s Role in Hepatocyte Development and HCC Progression: Under normal conditions, HNF4α supports healthy hepatocyte development by exerting direct (EMT via Snail/Slug) and indirect (chromatin modulation) effects. In HCC, HNF4α downregulation drives hepatocyte transformation, promoting EMT, metabolic reprogramming, and the Warburg effect, resulting in increased cancer cell proliferation, migration, and invasion. Created using BioRender (BioRender.com)

Fig. 3

HNF4α Restoration Reverses HCC Metabolism and Growth: Low level of HNF4α in HCC correlates with increased glycolysis, gluconeogenesis, cholesterol metabolism, and sulfur amino acid metabolism, leading to enhanced tumor growth, metastasis, and proliferation. Restoring HNF4α reverses these metabolic changes, resulting in smaller tumors with reduced metastatic potential. The therapeutic potential of HNF4α restoration warrants further investigation. Created with BioRender (BioRender.com)

Fig. 4

HNF4α regulates various pathways involved in HCC progression. HNF4α modulates cell death mechanisms, including ferroptosis, in which it decreases lipid peroxidation, and apoptosis via interactions with BAP31 and NF-κB. These pathways contribute to enhanced HCC survival and progression. Additionally, HNF4α influences the stemness CSC, as indicated by increased expression of CD133, promoting tumor recurrence and drug resistance. The combined effects enhance HCC survival, progression, and worsen clinical outcomes. Created with BioRender (BioRender.com)

Fig. 5

HNF4α Downregulation Drives Hepatocellular Carcinoma Proliferation and Genomic Instability: Downregulation of HNF4α promotes HCC progression through key molecular pathways. Reduced HNF4α leads to increased c-MYC activation, which suppresses p21 and subsequently elevates Cyclin D1, driving cell cycle progression and HCC proliferation. Additionally, increased Cyclin F expression due to HNF4α loss contributes to genomic instability. Both pathways converge to promote HCC proliferation. The red arrows indicate downregulation, while green arrows indicate upregulation. Created with BioRender (BioRender.com)

Fig. 6

HNF4α Depletion Mediated by p-STAT3 Signaling in Hepatocytes Drives Metabolic Disruption and HCC Progression: Pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α, secreted by macrophages and infiltrating T cells, activate the p-STAT3 signaling pathway in hepatocytes. This activation downregulates HNF4α, a key regulator of liver metabolism and tumor suppression. ultimately contributing to HCC progression. Created with BioRender (BioRender.com)

Fig. 7

Transcriptional control of HNF4α and its impact on HCC progression: HNF4α expression and activity are modulated by various transcription factors (KDM1A, WT1/P53, GSK-3β, YAP1, and GLUT4). Downregulation of HNF4α promotes HCC progression by increasing cell proliferation, liver fibrosis, and metastasis, while impairing DNA binding, tumor suppression, and cell survival, ultimately leading to worse outcomes. Created with BioRender (BioRender.com)