Natural molecule paeoniflorin acts as a gastric mucosal repair agent by targeting PTEN

Gastric mucosal injury is a common pathological condition significantly impacting patients' quality of life. Natural molecule paeoniflorin (Pae) shows the potential protective role in gastric injury.

To comprehensively demonstrate the therapeutic efficacy of Pae against gastric mucosal injury and elucidate its underlying molecular mechanism.

This study employed multifaceted approaches: evaluating Pae effects using ethanol-induced human gastric epithelial cells (GES-1), rat models in vivo, and human-derived gastric organoids ex vivo. Integrative techniques included RNA sequencing, HuProt™20 K human proteome microarray, MST, DARTS, Biotin-Pulldown, PTEN overexpression and knockdown studies, and pharmacological PTEN activation.

Pae significantly restored mucosal integrity by suppressing inflammation, alleviating oxidative stress, promoting mucosal repair factors, enhancing proliferation, and reducing apoptosis across all tested models. RNA-seq revealed Pae activates AKT/CREB signaling independent of PI3K to remodel the gastric tight junction barrier. HuProt™20 K proteomics identified PTEN as the direct target of Pae. PTEN knockdown alleviates GES-1 cell injury. Molecular validations, including MST, DARTS, and Biotin-Pulldown confirmed Pae specifically binds to the Pro169 residue within PTEN's phosphatase domain. This binding promoted PTEN ubiquitination, inhibited its membrane translocation, increased PIP3 accumulation, and consequently activated AKT/CREB signaling, driving tight junction and mucosal factor expression. Crucially, both PTEN overexpression and pharmacological PTEN activation abolished Pae's protective effects, confirming the essential role of targeting PTEN.

This work reveals a novel Pae-PTEN-AKT/CREB-mucosal barrier axis, establishing Pae as a promising therapeutic candidate for treating gastric mucosal injury by targeting PTEN.