Acute gastric mucosal injury impairs gastrointestinal homeostasis with limited clinical repair strategies. As a natural triterpenoid, limonin exerts gastric mucosal protection, while its precise target and mechanism remain elusive. We verified that limonin alleviated ethanol-induced gastric damage, suppressed inflammation and apoptosis, and promoted epithelial repair in rat models and GES-1 cells. Mechanistically, limonin directly binds USP7 at MET410 to strengthen the USP7-Rap1A interaction. It enhances USP7-mediated K31 deubiquitination to block K48-linked Rap1A proteasomal degradation, activating the Rap1A/Rac1 cascade. This signaling remodels epithelial tight junctions and cytoskeletons. Genetic and pharmacological USP7 inhibition abolished limonin’s protection, which was further validated in iPSC-derived gastric organoids. This study identifies a novel USP7-Rap1A axis underlying limonin’s gastroprotective effects.
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Hu et al. (2026) studied this question.
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