Resveratrol in oral cancer: a systematic review of preclinical studies on its anticancer mechanisms and therapeutic potential.

OBJECTIVE: Oral cancer remains a major global health challenge due to its aggressive nature, high recurrence rates, and limited treatment options. Resveratrol (RV), a naturally occurring polyphenol, has demonstrated promising anticancer properties in various malignancies, including oral cancer. This systematic review aimed to evaluate preclinical evidence on RV's therapeutic effects in oral cancer, focusing on its mechanisms of apoptosis induction, metastasis inhibition, autophagy regulation, and immune modulation. METHODS: A systematic review was conducted following PRISMA guidelines, with a comprehensive search in Google Scholar, PubMed, Embase, Scopus, and Web of Science for preclinical studies published up to March 2, 2025. Both in vitro and in vivo studies investigating RV's effects on oral cancer were included based on predefined inclusion and exclusion criteria. Data extraction was performed independently by multiple researchers, with discrepancies resolved through consensus. Key mechanisms of RV's anticancer activity, including apoptosis, metastasis suppression, autophagy, and immune regulation, were analyzed. RESULTS: Out of 346 studies screened, 19 (four in vivo and 15 in vitro) met the eligibility criteria. RV exhibited potent anticancer effects in a dose- and time-dependent manner, significantly reducing oral cancer cell viability and tumor growth in animal models. Mechanistically, RV induced apoptosis through caspase-3, -7, and -9 activation and modulation of pro-apoptotic (Bax, Bak) and anti-apoptotic (Bcl-2, Bcl-XL) proteins. RV also inhibited key oncogenic pathways, including Akt/mTOR and JAK2/STAT3, thereby suppressing tumor proliferation and immune evasion. Additionally, RV impaired metastatic progression by downregulating EMT-related transcription factors (TWIST, SLUG, and Zeb1) and reducing angiogenic markers such as VEGF and MMPs. Notably, RV induced autophagy in a dose- and time-dependent manner, as evidenced by increased LC3-II, Beclin1, and p62 expression. In cisplatin-resistant oral cancer models, RV promoted both apoptotic and autophagic cell death, suggesting its potential as an adjuvant therapy. CONCLUSION: This systematic review underscored the potential of RV as a promising anticancer agent for oral cancer. Through apoptosis induction, metastasis suppression, autophagy modulation, and immune regulation, RV demonstrated broad-spectrum anticancer effects. However, its low bioavailability remains a significant challenge. Future research should focus on optimizing drug delivery strategies, such as nanoparticle formulations and combination therapies, to enhance RV's therapeutic efficacy and facilitate clinical translation.