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

## TL;DR

Paeonol, a compound from Cortex Moutan, inhibits oral cancer growth by affecting the PI3K/AKT pathway and inducing cell death.

## Contribution

This study reveals Paeonol's dual role in inducing apoptosis and autophagy in oral cancer cells via the PI3K/AKT pathway.

## Key findings

- Paeonol inhibits OSCC cell proliferation and EMT by reducing PI3K/AKT phosphorylation.
- Paeonol induces mitochondrial apoptosis and protective autophagy in OSCC cells.
- Combining Paeonol with autophagy inhibitors enhances its antitumor effects.

## Abstract

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.

This study assessed the effects of Pae treatment on proliferation, migration, and invasive potential of OSCC cells in vitro. 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.

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.

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.