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Peer-reviewedCC BY 4.0Cancers

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

  • Camila Galeota Satini1,2,3
  • Barbara Bueloni1,2,4
  • Nicolás Marcolini1,2,5
  • Esteban Fiore1,2,3
  • Juan Bayo1,2,3
  • Guillermo Mazzolini1,2,3,6
6 affiliations
  1. 1Hepatology and Gene Therapy Program, Instituto de Investigaciones en Medicina Traslacional, CONICET-Universidad Austral, Av. Pte. Perón 1500, Pilar B1629AHJ, Buenos Aires, Argentina
  2. 2Facultad de Ciencias Biomédicas, Universidad Austral, Av. Pte. Perón 1500, Pilar B1629AHJ, Buenos Aires, Argentina
  3. 3Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Av. Rivadavia 1917, Buenos Aires C1033AAJ, Argentina
  4. 4Spectrum Regenerative (HZ4 Liver Inc.), Miami, FL 33130, USA
  5. 5Oncology Service, Hospital Universitario Austral, Universidad Austral, Av. Pte. Perón 1500, Pilar B1629AHJ, Buenos Aires, Argentina
  6. 6Liver Unit, Hospital Universitario Austral, Universidad Austral, Av. Pte. Perón 1500, Pilar B1629AHJ, Buenos Aires, Argentina
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{satini2026smyd2,
  title = {{SMYD2 in Hepatocellular Carcinoma: An Emerging Epigenetic Link Between Tumor Cell Programs and Microenvironmental Dynamics}},
  author = {Camila Galeota Satini and Barbara Bueloni and Nicolás Marcolini and Esteban Fiore and Juan Bayo and Guillermo Mazzolini},
  journal = {Cancers},
  year = {2026},
  month = nov,
  doi = {10.3390/cancers18213586},
  url = {https://www.mdpi.com/2072-6694/18/21/3586},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - SMYD2 in Hepatocellular Carcinoma: An Emerging Epigenetic Link Between Tumor Cell Programs and Microenvironmental Dynamics
AU  - Camila Galeota Satini
AU  - Barbara Bueloni
AU  - Nicolás Marcolini
AU  - Esteban Fiore
AU  - Juan Bayo
AU  - Guillermo Mazzolini
PY  - 2026
DA  - 2026/11/08
JO  - Cancers
DO  - 10.3390/cancers18213586
UR  - https://www.mdpi.com/2072-6694/18/21/3586
AB  - 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.
SN  - 2072-6694
ER  -