Traditional wisdom to modern science: Hesperetin and naringenin as emerging traditional Chinese medicine-based treatments for Alzheimer’s disease

• Naringenin and hesperetin are abundant in common Chinese fruits, Citrus maxima (Pummelo), Citrus sinensis (sweet orange), and Citrus reticulata (mandarin) • This review, elaborates the neurotherapeutic properties of Naringenin and hesperetin and its active application in traditional Chinese medicine (TCM) • Naringenin and hesperetin exhibit neuroprotection by improving brain biogenic amines and modulating Wnt/β-catenin and Keap1/Nrf2 • Clinical trials on naringenin and hesperetin indicate their potential in the treatment of Alzheimer’s disease. : Hesperetin and naringenin are the two flavonoids that are widely applied in Traditional Chinese Medicine (TCM) and mostly found in citrus fruits. Both flavonoids have shown considerable neuroprotective potential. These substances originate from glycosidic precursors, hesperidin and naringin, which are chiefly found in medicinal plants like Zanthoxylum avicennae and Citrus reticulata . In TCM, these botanicals are historically utilized for their analgesic, anti-inflammatory, and digestive properties, but their potential in influencing neurodegenerative processes is receiving growing scrutiny. : The aim of this review is to cumulate the neuroprotective properties by systematically retrieving the peer-reviewed preclinical and clinical trial research and studies performed in hesperetin and naringenin on multiple mechanisms connected with AD. : A complete systematic review has been employed by applying MeSH search terms through the application of keywords such as “Alzheimer’s Disease”, “Neuroprotection”, “amyloid”, molecular mechanistic pathways of AD which are discussed in this review and “Clinical trials” for the polyphenols naringenin and hesperetin. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) analysis method was used for screening of the research studies conducted on naringenin and hesperetin. : The review retrieved 312 articles in respect to the hesperetin and naringenin on neurodegenerative diseases related to AD. Further scrutinised to 87 with terms of decrease of amyloid-beta aggregation, prevention of tau hyperphosphorylation, mitigation of oxidative stress, and suppression of neuroinflammation. Furthermore, they affect essential molecular cascades, including the PI3K/AKT, NRF2/ARE, and NF-κB signalling pathways, which are intricate for neuronal survival and cognition. It was also found that their ability to cross the blood-brain barrier further amplifies their pharmacological significance in central nervous system illnesses. : Hesperetin and naringenin, as natural multifunctional agents derived from traditional practices, present intriguing opportunities for integrative treatment approaches to AD, connecting the insights of TCM with contemporary neuropharmacology. Further, our review reveals several mechanisms; hesperetin and naringenin are yet to be evaluated in aspects of the hypothalamic-pituitary-adrenal axis (HPA) associated with the stress pathway of neurodegeneration, and exploring the HPA renders additional mechanistic neuroprotective recognition.