Targeting super enhancers for liver disease: a review

Super enhancers (SEs) refer to the ultralong regions of a gene accompanied by multiple transcription factors and cofactors and strongly drive the expression of cell-type-related genes. Recent studies have demonstrated that SEs play crucial roles in regulating gene expression related to cell cycle progression and transcription. Aberrant activation of SEs is closely related to the occurrence and development of liver disease. Liver disease, especially liver failure and hepatocellular carcinoma (HCC), constitutes a major class of diseases that seriously endanger human health. Currently, therapeutic strategies targeting SEs can dramatically prevent disease progression and improve the prognosis of animal models. The associated new approaches to the treatment of related liver disease are relatively new and need systematic elaboration.

In this review, we elaborate on the features of SEs and discuss their function in liver disease. Additionally, we review their application prospects in clinical practice in the future. The article would be of interest to hepatologists, molecular biologists, clinicians, and all those concerned with targeted therapy and prognosis of liver disease.

We searched three bibliographic databases (Web of Science Core Collection, Embase, PubMed) from 01/1981 to 06/2022 for peer-reviewed scientific publications focused on (1) gene treatment of liver disease; (2) current status of SE research; and (3) targeting SEs for liver disease. We included English language original studies only.

The number of published studies considering the role of enhancers in liver disease is considerable. Since SEs were just defined in 2013, the corresponding data on SEs are scarce: approximately 50 papers found in bibliographic databases on the correlation between enhancers (or SEs) and liver disease. Remarkably, half of these papers were published in the past three years, indicating the growing interest of the scientific community in this issue. Studies have shown that treatments targeting components of SEs can improve outcomes in liver disease in animal and clinical trials.

The treatment of liver disease is facing a bottleneck, and new treatments are needed. Therapeutic regimens targeting SEs have an important role in the treatment of liver disease. However, given the off-target effect of gene therapy and the lack of clinical trials, the available experimental data are still fragmented and controversial.