Natural Products and Long Noncoding RNAs: A Complex Regulatory Network in Pancreatic Cancer Progression and Treatment

Pancreatic cancer (PC) is among the most lethal malignancies, characterized by late-stage diagnosis, limited treatment options, and high therapeutic resistance. Growing evidence indicates that long noncoding RNAs (lncRNAs) are key regulators of PC pathogenesis, influencing tumor initiation, progression, and resistance mechanisms. This review comprehensively examines the biogenesis and molecular functions of lncRNAs, with a focus on their regulation through critical oncogenic pathways, including PI3K/Akt, JAK/STAT, and Wnt/β-catenin. The roles of lncRNAs in promoting epithelial-mesenchymal transition (EMT), invasion, proliferation, apoptosis evasion, angiogenesis, and metastasis are detailed, as these processes underpin disease progression and poor clinical outcomes. In addition, lncRNAs have emerged as central mediators of therapy resistance, contributing to the failure of chemotherapy, radiotherapy, and immunotherapy in PC. Natural compounds have demonstrated the capacity to modulate key oncogenic pathways involved in PC pathogenesis, thereby presenting promising adjunctive strategies to improve therapeutic efficacy. The clinical significance of lncRNAs is further explored, particularly their potential utility as diagnostic and prognostic biomarkers. Insights into posttranscriptional regulation of lncRNA expression add another layer of complexity to their biological roles. By integrating emerging data across these domains, this review highlights the multifaceted contributions of lncRNAs to PC biology and identifies promising avenues for future therapeutic development and biomarker discovery.