Curcumin-based compounds in non-malignant biliary injury and cholangiocarcinoma: mechanistic insights and translational barriers.

Biliary tract diseases are frequently associated with chronic cholestasis, cholangiocyte injury, inflammation, and fibrotic remodeling. Persistent injury and dysregulated repair may create a microenvironment that promotes the development of cholangiocarcinoma (CCA). CCA is an aggressive and highly heterogeneous biliary malignancy shaped by the interplay among bile acid dysregulation, inflammatory signaling, oxidative and nitrative stress, metabolic adaptation, stromal remodeling, and therapeutic resistance. Curcumin, a major bioactive polyphenol derived from Curcuma longa, and related curcumin-based compounds have been investigated in preclinical studies for their anti-inflammatory, antioxidant, antifibrotic, and antitumor properties. Available evidence suggests that native curcumin, its analogs and derivatives, and formulation-based interventions may modulate signaling pathways involved in chronic biliary injury and CCA progression, including NF-κB, Nrf2/HO-1, and TGF-β/Smad signaling. However, the therapeutic application of native curcumin is limited by poor aqueous solubility, low oral bioavailability, rapid metabolism, and inadequate tissue-specific delivery. This review critically evaluates curcumin-based interventions across non-malignant biliary injury and established CCA, with emphasis on their proposed mechanisms, delivery strategies, evidence limitations, and translational barriers. Current evidence remains predominantly preclinical, and curcumin-based interventions should therefore be regarded as experimental candidates rather than established therapies.