Citrus flavanones (Naringenin, Hesperidin, and Hesperetin) in oral and gastric carcinogenesis: Mechanistic insights into oxidative stress, cell death, epigenetic regulation, non-coding RNAs, and tumor microenvironment remodeling

Abstract

Flavonoids derived from citrus fruits, including naringenin, naringin, hesperetin, and hesperidin, represent a class of dietary bioactives with potential chemopreventive properties against oral cancer and gastric cancer (GC). However, previous reviews have largely focused on isolated molecular pathways or single cancer types, lacking an integrated comparison of oral and gastric carcinogenesis within a unified mechanistic framework. Preclinical investigations using chemical carcinogenesis models consistently show that these compounds attenuate oxidative stress, restore cellular redox balance, and modulate critical regulators of apoptosis, proliferation, and survival. Nanoparticle-based delivery enhances bioavailability, tissue targeting, and pharmacokinetics, amplifying anti-proliferative, pro-apoptotic, and antioxidant effects. In oral carcinoma models, flavonoids promote cell cycle arrest, apoptosis, and autophagy, while reinforcing chemosensitivity. In GC systems, they reduce proliferation, migration, and invasion. Additionally, these compounds influence the tumor microenvironment (TME) by modulating immune surveillance, suppressing PD-L1 expression, restraining angiogenesis, and interacting with microbial and inflammatory pathways. Epigenetic and non-coding RNA mechanisms, including DNA methylation, microRNA, and long non-coding RNA regulation, further contribute to cytostatic and antimetastatic outcomes. Unlike previous reports, this review integrates intracellular signaling, TME modulation, epigenetic regulation, and nanodelivery strategies across both oral and GC models, providing a unified multi-layered mechanistic framework. Collectively, these findings delineate a multi-layered mechanistic framework for citrus flavonoids, supporting their promise as adjunctive chemopreventive agents while emphasizing the necessity for translational and clinical validation.