Curcumin scaffold to dual NF-κB/STAT3 modulators: advancing strategies against chemotherapy-resistant colorectal cancer

Chemotherapy resistance in colorectal cancer is driven by interconnected inflammatory and survival pathways rather than isolated molecular alterations. Among these, nuclear factor kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) form a cooperative signaling axis that sustains apoptosis evasion, stem-like phenotypes, and poor response to chemotherapy. Curcumin has emerged as a multi-target bioactive scaffold capable of modulating both pathways, but its therapeutic translation is limited by poor bioavailability and unfavorable pharmacokinetics. This review examines how structural optimization of the curcumin scaffold has generated analogues with improved stability, potency, and pathway selectivity for overcoming chemoresistance in colorectal cancer. Particular emphasis is placed on monocarbonyl analogues, fluorinated derivatives, heterocyclic compounds, and prodrug-based designs, with discussion of how scaffold modification influences target engagement and biological response. Docking studies are considered as structural support for pathway modulation when interpreted alongside biological findings. Delivery strategies, translational barriers, early clinical evidence, biomarker-guided development, and emerging artificial intelligence-assisted design are also discussed. Preclinical evidence indicates that structurally optimized curcumin analogues more effectively suppress NF-κB/STAT3 signaling, restore chemosensitivity, and disrupt resistance-associated survival programs in colorectal cancer. Collectively, these analogues represent promising mechanism-driven candidates for overcoming chemoresistance and provide a valuable platform for future translational development.