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Peer-reviewedCC BYFrontiers in cell and developmental biology

Crosstalk between PI3K/AKT signaling and epigenetic regulation in hepatocellular carcinoma: molecular mechanisms and therapeutic opportunities

  • Zhibo Zhang1
  • Jie Liu2
  • Guofeng Lei3
  • Xinjun Hu1
  1. 1The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology , , ,
  2. 2The First Affiliated Hospital of Zhengzhou University , , ,
  3. 3Yellow River Sanmenxia Hospital Affiliated to Henan University of Science and Technology , , ,
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Abstract

Hepatocellular carcinoma (HCC) is an aggressive malignancy, and most patients are diagnosed at intermediate or advanced stages. Targeted therapies, immunotherapies, and combination regimens have limited efficacy, creating a major clinical challenge. The phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway is frequently and persistently activated in HCC. Epigenetic modifications regulate gene expression without altering the DNA sequence and contribute to malignant progression. Aberrant epigenetic states sustain PI3K/AKT activation by silencing tumor-suppressor genes and activating oncogenic signaling. Conversely, activated PI3K/AKT signaling remodels the epigenome through several enzymes that mediate epigenetic modifications. This bidirectional interaction promotes HCC progression. This review examines how DNA methylation, non-coding RNAs, and histone modifications drive excessive PI3K/AKT pathway activation. It also assesses the more limited evidence that PI3K/AKT signaling regulates these enzymes and reviews recent progress in combining PI3K inhibitors with epigenetic-targeting agents. We then consider the main barriers to clinical translation, including biomarker selection, treatment scheduling, and nanocarrier-based co-delivery. Clarifying this reciprocal regulation may support more rational, individualized therapeutic strategies for HCC.

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Cite

BibTeXRIS
BibTeX
@article{zhang2026crosstalk,
  title = {{Crosstalk between PI3K/AKT signaling and epigenetic regulation in hepatocellular carcinoma: molecular mechanisms and therapeutic opportunities}},
  author = {Zhibo Zhang and Jie Liu and Guofeng Lei and Xinjun Hu},
  journal = {Frontiers in cell and developmental biology},
  year = {2026},
  month = oct,
  doi = {10.3389/fcell.2026.1975140},
  url = {https://europepmc.org/article/PMC/PMC13727954},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Crosstalk between PI3K/AKT signaling and epigenetic regulation in hepatocellular carcinoma: molecular mechanisms and therapeutic opportunities
AU  - Zhibo Zhang
AU  - Jie Liu
AU  - Guofeng Lei
AU  - Xinjun Hu
PY  - 2026
DA  - 2026/10/20
JO  - Frontiers in cell and developmental biology
DO  - 10.3389/fcell.2026.1975140
UR  - https://europepmc.org/article/PMC/PMC13727954
AB  - Hepatocellular carcinoma (HCC) is an aggressive malignancy, and most patients are diagnosed at intermediate or advanced stages. Targeted therapies, immunotherapies, and combination regimens have limited efficacy, creating a major clinical challenge. The phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway is frequently and persistently activated in HCC. Epigenetic modifications regulate gene expression without altering the DNA sequence and contribute to malignant progression. Aberrant epigenetic states sustain PI3K/AKT activation by silencing tumor-suppressor genes and activating oncogenic signaling. Conversely, activated PI3K/AKT signaling remodels the epigenome through several enzymes that mediate epigenetic modifications. This bidirectional interaction promotes HCC progression. This review examines how DNA methylation, non-coding RNAs, and histone modifications drive excessive PI3K/AKT pathway activation. It also assesses the more limited evidence that PI3K/AKT signaling regulates these enzymes and reviews recent progress in combining PI3K inhibitors with epigenetic-targeting agents. We then consider the main barriers to clinical translation, including biomarker selection, treatment scheduling, and nanocarrier-based co-delivery. Clarifying this reciprocal regulation may support more rational, individualized therapeutic strategies for HCC.
SN  - 2296-634X
ER  -