Abstract

TSA exerts protective effects against acute pancreatitis by improving impaired autophagic flux. • TSA reduces ERK phosphorylation, which may be associated with modulation of FoxO3a phosphorylation status. • Modulation of FoxO3a-associated signaling is accompanied by improvement of impaired autophagic flux in AP. • ERK activation attenuates the protective effects of TSA, supporting the involvement of the ERK/FoxO3a signaling axis. • The ERK/FoxO3a axis may represent a potential therapeutic target in acute pancreatitis. Acute pancreatitis (AP) is an inflammatory disease with increasing incidence and limited therapeutic options. Impaired autophagic flux is recognized as a key pathological event in AP, while its upstream regulatory mechanisms remain incompletely understood. FoxO3a, a transcription factor involved in autophagy regulation, is negatively regulated by ERK-mediated phosphorylation. This study investigated whether Trichostatin A (TSA), a histone deacetylase inhibitor, protects against AP through modulation of the ERK/FoxO3a axis. Network pharmacology, protein–protein interaction analysis, and enrichment analyses identified the ERK/FoxO3a pathway as a potential target of TSA. In AR42J cells, TSA was combined with the autophagy inhibitor 3-MA or the ERK activator PMA to validate the underlying mechanisms. Autophagic flux, inflammatory cytokines, mitochondrial function, and related protein expression were assessed, and a rat model of AP was used for in vivo validation. TSA improved impaired autophagic flux and alleviated AP-associated injury. ERK phosphorylation was significantly increased under AP conditions, while FoxO3a expression showed a modest increase, suggesting possible regulatory adaptation and functional suppression under stress conditions. TSA treatment was associated with reduced ERK phosphorylation and modulation of FoxO3a-associated signaling, and was accompanied by improvement of impaired autophagic flux. These effects were partially reversed b