Molecular effects of areca nut-derived compounds on human oral cancer cells: a systematic review of in vitro evidence.

Objective: Areca nut chewing is a major risk factor for oral potentially malignant disorders (OPMD) and oral squamous cell carcinoma (OSCC), yet the molecular mechanisms underlying its carcinogenic effects remain incompletely integrated. This systematic review aimed to synthesize in vitro evidence on the molecular effects of areca nut extract and areca nut-derived alkaloids in human oral cancer cells. Methods: This systematic review followed PRISMA 2020. PubMed, ScienceDirect, and Scopus were searched from inception to the final search date. Eligible studies used human oral squamous cell carcinoma cell lines or primary oral cancer cells exposed to areca nut extract or related compounds. Outcomes involving inflammation, proliferation, oxidative stress, oncogenic signaling, and tumor-suppressor regulation were qualitatively synthesized because of methodological heterogeneity. Results: Twenty studies met the inclusion criteria. Areca nut-derived compounds were associated with increased pro-inflammatory mediators, including IL-1β, IL-6, IL-8, COX-2, and PGE2. They also altered cell proliferation and cell-cycle control, with increased proliferative markers and suppression of key checkpoint regulators. Oxidative stress was characterized by elevated intracellular and mitochondrial reactive oxygen species, oxidative DNA damage, lipid peroxidation, and impaired antioxidant defenses. Oncogenic and stress-responsive pathways, including NOTCH1, Akt, and Nrf2/HO-1, were activated, whereas p53, p27, SIRT1, and AP-1 transcription factors were downregulated. Findings for p21 were contradictory across studies. Conclusions: In vitro evidence indicates that areca nut constituents induce coordinated inflammatory, proliferative, oxidative, and signaling alterations that support their carcinogenic role in human oral cancer cells.