Naringenin exhibits anti-inflammatory and immunomodulatory activities in pancreatic cancer modelsNaringenin Shows Potential for Managing Pancreatic Cancer Cells

Pancreatic cancer continues to be among the deadliest malignancies because of its aggressive biology, dense stromal structure, profound immunosuppression, and restricted responsiveness to existing treatment approaches. Accumulating evidence indicates that effective intervention likely depends on coordinated regulation of the tumor immune–stromal microenvironment, metabolic plasticity, and host–tumor interactions, rather than on malignant-cell targeting alone. Naringenin, a naturally occurring citrus flavanone, has received increasing attention due to its wide-ranging biological effects, including anti-inflammatory, antioxidant, immunomodulatory, and metabolic regulatory activities. This narrative review critically evaluates the current evidence on the molecular mechanisms through which naringenin affects pancreatic cancer progression, with a particular focus on tumor immune–stromal interactions, immunometabolic reprogramming, microbiota–host signaling, and therapeutic resistance. We examine its effects on oncogenic signaling pathways, immune cell function, cancer-associated fibroblasts, extracellular matrix remodeling, oxidative stress, mitochondrial homeostasis, and regulated cell death, while emphasizing growing evidence that connects dietary polyphenols with gut microbiota-derived metabolites and systemic immune regulation. The review also assesses the potential of naringenin as an adjuvant to conventional chemotherapy, targeted therapy, and immunotherapy, while recognizing the constraints arising from low bioavailability, heterogeneous preclinical models, and limited clinical evidence. Finally, we highlight key knowledge gaps and outline future research priorities, including biomarker-guided patient stratification, advanced drug delivery systems, and translational studies that combine multi-omics technologies with mechanistic investigations. Improved understanding of these interrelated mechanisms may support the rational development of naringenin-based therapeutic strategies for pancreatic cancer.