HCC is the most widespread variant of primary liver cancer and ranks among the leading causes of cancer-related mortality worldwide, accounting for over 800,000 deaths annually (Arnold et al., 2020). The multifactorial etiology of HCC includes chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, alcohol consumption, metabolic dysfunction-associated steatotic liver disease (MASLD), and aflatoxin B1 exposure (Rahimi-Farsi et al., 2025). Despite advances in surgical resection, liver transplantation, and systemic therapies such as tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs), HCC remains highly refractory to treatment, with a five-year survival rate below 20 % for advanced cases (Kudo et al., 2018). One of the primary challenges in HCC management is the molecular complexity and heterogeneity of the disease, which is driven by multiple oncogenic signaling pathways. Among these, the c-MYC proto-oncogene has emerged as a critical regulator of tumor initiation, progression, and therapeutic resistance in HCC (Schaub et al., 2018).

c-MYC acts as a fundamental transcription factor overseeing a range of biological functions, such as cell cycle progression, metabolism, apoptosis, and genomic stability. Overexpression of c-MYC has been detected in approximately 30–50 % of HCC cases and is frequently associated with aggressive tumor behavior, high proliferative capacity, and failure to respond to chemotherapy and targeted therapeutics (Min et al., 2021, Ben Rejeb et al., 2025, Hushmandi et al., 2024). Mechanistically, c-MYC regulates hepatocarcinogenesis by orchestrating multiple oncogenic signaling networks, including the PI3K/Akt/mTOR, Wnt/β-catenin, and MAPK/ERK pathways; each of these components plays a role in ensuring tumor cell survival, angiogenesis, and immune evasion (Chen et al., 2020, Ladu et al., 2008) Additionally, c-MYC is essential in orchestrating metabolic reprogramming by promoting glycolysis (the Warburg effect), glutaminolysis, and lipid metabolism to fulfill the high metabolic demands of rapidly growing tumor cells (Li et al., 2024a). These oncogenic functions highlight the importance of c-MYC as a therapeutic target in HCC.

Despite its pivotal role in cancer progression, directly targeting c-MYC has remained challenging due to its intrinsically disordered protein structure, lack of a defined ligand-binding pocket, and rapid turnover (Delmore et al., 2011). Consequently, current therapeutic strategies focus on indirect approaches, such as inhibiting upstream regulators, blocking c-MYC transcription and translation, destabilizing c-MYC protein, or disrupting its interactions with cofactors (Pinter et al., 2023). One promising strategy involves targeting bromodomain and extra-terminal (BET) proteins, which are essential for c-MYC transcriptional activation, with small-molecule inhibitors like JQ1 and I-BET762 (Filippakopoulos et al., 2010). Other approaches include the inhibition of cyclin-dependent kinase 9 (CDK9), which is required for c-MYC mRNA elongation, and proteolysis-targeting chimeras (PROTACs) designed to degrade c-MYC protein (Olson et al., 2018). Additionally, emerging evidence suggests that metabolic interventions targeting glucose and glutamine metabolism may selectively suppress c-MYC-driven HCC while sparing normal hepatocytes (Liu et al., 2023).

Given the growing understanding of c-MYC’s oncogenic functions and the recent advancements in targeted therapies, a prompt need is evident to develop effective strategies to inhibit c-MYC-driven hepatocarcinogenesis. This review delivers a detailed exploration of the molecular mechanisms c-MYC promotes HCC progression and explores potential therapeutic approaches to disrupt c-MYC activity. By elucidating these mechanisms, this work aims to identify novel vulnerabilities in c-MYC-driven HCC, paving the way for innovative and more effective treatment strategies.