From mechanism to clinic: the potential and challenges of HDAC1 in cholangiocarcinoma treatment

Abstract Cholangiocarcinoma (CCA) is a malignant tumor originating from the biliary epithelium, with global incidence and mortality rates on the rise. Due to difficulties in early diagnosis and the fact that most patients are diagnosed at an advanced stage, the prognosis for CCA is extremely poor. Currently, gemcitabine combined with cisplatin serves as the first-line regimen for advanced CCA, but its clinical efficacy is significantly limited by drug resistance. Therefore, there is an urgent need to identify new therapeutic targets. Epigenetic abnormalities are a critical feature in the development and progression of CCA, among which the imbalance of histone acetylation and deacetylation is particularly crucial. Histone Deacetylase 1 (HDAC1), as a core member of class I HDAC family, is frequently overexpressed in CCA and closely associated with adverse patient outcomes. Various HDAC inhibitors have shown effectiveness in inhibiting tumor cell growth and inducing cell death, and the combination therapy of HDAC inhibitors with other anticancer drugs has demonstrated broad prospects. Thus, HDAC1 represents a promising epigenetic target in CCA treatment. In-depth analysis of the specific molecular mechanisms of HDAC1 in cholangiocarcinoma, development of highly selective HDAC1 inhibitors and exploration of optimized combination strategies of HDAC1 inhibitors with chemotherapy, immunotherapy and other targeted therapies can provide more precise and effective treatment options for CCA patients, thereby improving their prognosis.