SMYD2 in Hepatocellular Carcinoma: An Emerging Epigenetic Link Between Tumor Cell Programs and Microenvironmental Dynamics

Hepatocellular carcinoma (HCC) usually arises within chronically injured liver tissue, where inflammation, fibrosis, metabolic dysfunction, and immune remodeling shape tumor evolution and therapeutic response. This biological complexity has increased interest in regulators capable of connecting tumor-intrinsic programs with the diseased hepatic microenvironment. SET and MYND domain-containing protein 2 (SMYD2) is a lysine methyltransferase that modifies histone and non-histone substrates involved in transcriptional control, tumor suppressor regulation, DNA damage repair, metabolism, cellular plasticity, and inflammatory signaling. In HCC, increased SMYD2 expression has been associated with aggressive clinicopathological features and poor outcome, while functional studies link SMYD2 to tumor cell proliferation, c-Myc/GLS1-dependent glutamine metabolism, stemness-associated programs, sorafenib resistance, and immune evasion. Mechanistically, SMYD2 may act through multiple context-dependent pathways, including β-catenin methylation, BMP4/SMAD/ID3 signaling, TLR4/NF-κB-dependent hepatic stellate cell activation, and Wnt ligand-mediated tumor–macrophage communication, leading to TGF-β-associated immune suppression. In preclinical HCC models, SMYD2 inhibition has reduced tumor growth and enhanced responses to sorafenib or anti-PD-1 treatment, although its clinical efficacy and safety remain to be established. This translational uncertainty is particularly relevant because SMYD2 dependency is not uniform across cancer models, and its functions in non-tumoral liver, macrophages, and acute hepatic injury suggest that systemic inhibition may have compartment- and context-specific consequences. This review summarizes the structural basis, biological functions, and therapeutic implications of SMYD2 in HCC, emphasizing both its mechanistic relevance and the questions that will need to be resolved before clinical translation.