Integrative Molecular Insights Into Epidemiological, Genetic, and Metabolic Risk Factors of Gallbladder Cancer: Implications for Biomarkers, Therapeutic Targeting, and Future Perspectives

Abstract

Gallbladder cancer (GBC) is a rare yet highly aggressive malignancy of the biliary tract, characterized by a five-year survival rate of less than 5%. Its asymptomatic onset and the lack of reliable early diagnostic tools contribute to delayed detection and poor clinical outcomes. Although epidemiological and genetic studies have identified numerous risk factors, the molecular mechanisms linking these factors to tumor initiation and progression remain incompletely understood. This review integrates current evidence on the multifactorial etiology of GBC—including geographic variation, genetic predisposition, environmental exposures, chronic inflammation, and infections—with emerging insights into metabolic and molecular dysregulation. Particular focus is placed on metabolic reprogramming as a central driver of carcinogenesis. Altered lipid metabolism, bile acid signaling, and redox imbalance interact with inflammatory and oncogenic pathways, fostering a permissive microenvironment for malignant transformation. Key molecular cascades include inflammation-driven NF-κB activation, bile acid–induced oxidative stress, PI3K/AKT-mediated metabolic remodeling, and DNA damage and repair defects. By consolidating diverse epidemiological and mechanistic data into a unified molecular–metabolic framework, this narrative review identifies new opportunities for biomarker discovery, metabolic imaging, early detection, and targeted therapeutic development, advancing translational research to improve outcomes in this devastating disease.