Paeonol inhibits the development of oral squamous cell carcinoma through the PI3K/AKT signaling pathway

Background: Paeonol (Pae), a phenolic bioactive compound extracted from Cortex Moutan, exhibits numerous pharmacological properties, including anti-inflammatory, immunomodulatory, and antitumor activities. However, the precise mechanisms by which Pae influences protective autophagy in oral squamous cell carcinoma (OSCC) remain incompletely characterized. Methods: . Network pharmacology was employed to identify potential molecular targets of Pae involved in OSCC. Autophagic flux was analyzed using transmission electron microscopy alongside a dual-fluorescence reporter assay. Additionally, the combined effects of Pae with autophagy inhibitors were investigated. Results: Pae treatment promoted mitochondrial-dependent apoptosis and effectively inhibited epithelial-mesenchymal transition (EMT) by attenuating phosphorylation within the PI3K/AKT signaling pathway. Pae simultaneously initiated protective autophagy, confirmed by intact autophagic flux observed in CAL-27 and HSC-3 cells. Interference with this autophagic process through the autophagy inhibitor 3-methyladenine (3-MA) intensified apoptotic activity and markedly reduced OSCC cell proliferation. Conclusion: Pae suppressed OSCC cell proliferation and EMT and was associated with mitochondrial apoptosis and activation of autophagic flux, accompanied by reduced PI3K/AKT phosphorylation. Co-treatment with 3-methyladenine (3-MA) further decreased cell viability and enhanced apoptosis-associated changes, suggesting that pharmacological co-targeting of PI3K signaling and autophagy may potentiate Pae's antitumor activity. Further studies are warranted to delineate the relative contributions of apoptosis and autophagy to Pae-induced cytotoxicity in OSCC.