Curcumin in pancreatic cancer: A comprehensive review of anticancer mechanisms, EMT modulation, and clinical challenges.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, characterized by aggressive local invasion, early metastasis, and profound chemoresistance. Epithelial-mesenchymal transition (EMT) is a critical driver of these aggressive phenotypes, promoting tumor cell dissemination and therapeutic failure. Curcumin, a naturally occurring polyphenol derived from Curcuma longa, has emerged as a promising adjunctive agent due to its ability to modulate diverse molecular pathways, including those governing EMT. METHODS: In this review, we synthesized findings from published studies investigating the anti-EMT effects of curcumin and its analogs in PDAC. Data were extracted from in vitro, in vivo, and clinical studies, focusing on molecular mechanisms, signaling pathways, non-coding RNA networks, and therapeutic outcomes. RESULTS: Curcumin and its synthetic analogs suppress EMT in PDAC cells through multiple interconnected mechanisms, including inhibition of TGF-β/Smad, Hedgehog, PI3K/Akt/NF-κB, and IL-6/ERK/NF-κB signaling pathways. These effects are accompanied by upregulation of epithelial markers (E-cadherin) and downregulation of mesenchymal markers (vimentin, Snail, Slug), leading to reduced migration, invasion, and metastasis. Curcumin also modulates the tumor microenvironment by reversing the mesenchymal phenotype of cancer-associated fibroblasts and inhibiting stellate cell-induced EMT. A number of non-coding RNAs, including miRNAs (miR-7, miR-340, miR-221), lncRNAs (PVT1), and circRNAs (circ_0001535, circ_0079440) are associated the anti-EMT, anti-cancer or chemosensitizing effects of curcumin. Curcumin enhances the sensitivity of PDAC cells to gemcitabine, cisplatin, and TRAIL-induced apoptosis. However, clinical translation is limited by poor oral bioavailability and gastrointestinal tolerability at high doses, though nanoparticle-based formulations and analogs show improved pharmacokinetic profiles. CONCLUSIONS: Curcumin exerts potent anti-EMT effects in PDAC through multi-targeted regulation of signaling pathways, non-coding RNAs, and stromal-tumor interactions. These findings support further investigation of optimized formulations and combination strategies to overcome the pharmacokinetic limitations and translate curcumin's preclinical promise into clinical benefit for pancreatic cancer patients.