Ferroptosis: A Novel Mechanistic Insight and Therapeutic Opportunity in Cholangiocarcinoma

Abstract

Cholangiocarcinoma, a malignancy of the biliary tract, remains one of the most lethal cancers with limited treatment options and poor prognosis. Emerging evidence indicates that ferroptosis an iron-dependent, oxidative form of regulated cell death, is a promising therapeutic vulnerability in Cholangiocarcinoma (CCA). This review presents an in-depth analysis of the molecular mechanisms driving ferroptosis, including iron metabolism, lipid peroxidation, and the glutathione/glutathione peroxidase 4 (GPX4) axis. It also explores the complex regulation of ferroptosis by key molecules including p53, TP53-induced glycolysis and apoptosis regulator (TIGAR), and noncoding RNAs within the CCA context. Recent computational and experimental studies have identified ferroptosis-related gene signatures and biomarkers that correlate with prognosis and therapeutic response. Moreover, ferroptosis inducers including small molecules like erastin, ras-selective lethal small molecule 3 (RSL3), and artesunate, have demonstrated potent anticancer effects in preclinical models. Nanotechnology-based strategies and gene-editing approaches offer novel delivery systems to enhance ferroptotic responses while minimizing systemic toxicity. The tumor microenvironment, particularly inflammation and immune components, further modulates ferroptosis and presents opportunities for combination therapies. This review concludes that targeting ferroptosis represents a novel and multifaceted therapeutic strategy for CCA, with the potential to synergize with chemotherapy, immunotherapy, and nanomedicine. Continued investigation into ferroptosis regulation and precision-based delivery systems could usher in a new era of effective treatments for this challenging malignancy.