Targeting oncogenic signaling pathways in lung cancer: the emerging role of nobiletin, a flavonoid from citrus peel

Lung cancer continues to have a high incidence rate, exhibiting a five-year overall survival percentage of merely 18.6 %. Despite advancements in conventional therapeutic approaches, drug resistance and treatment-associated toxicities remain major challenges. Recent research has focused on plant-derived molecules as promising therapeutic alternatives due to their low toxicity and significant anticancer effects. Nobiletin, a flavonoid enriched with polymethoxylated groups present in citrus peel, has exhibited diverse therapeutic properties, including antioxidants, immunomodulatory, neuroprotective, and antitumor activities. This review highlights anti-lung cancer activity of nobiletin by modulating critical tumor-promoting signaling pathways thereby suppressing cancer cell proliferation, infiltration, and metastasis. Most importantly, nobiletin triggers cancer cell apoptosis by caspase-3 activation and poly-(ADP-ribose) polymerase cleavage and functions as a key regulator in mitigating drug resistance by regulating various signaling pathways. However, its medical use is constrained by poor aqueous solubility and limited bioavailability. To mitigate these challenges, advanced drug delivery systems have been explored, including polymeric nanoparticles, nano-dispersed solids, micelles, and nano emulsions. Nanotechnology-based formulations such as self-micro emulsifying drug delivery systems, chitosan-based microemulsions, and liposomal encapsulation have significantly improved the nobiletin's stability, solubility, and targeted delivery. These approaches enhance its therapeutic efficacy, positioning nobiletin as a potential therapeutic strategy for lung cancer treatment.