Trichostatin A improves impaired autophagic flux associated with ERK/FoxO3a signaling to alleviate 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 by PMA. Consistently, TSA reduced serum amylase, TNF-α, and IL-6 levels and improved pancreatic histopathology. In conclusion, TSA alleviates AP-associated injury by improving impaired autophagic flux, which may be associated with inhibition of ERK phosphorylation and modulation of FoxO3a-related signaling. These findings highlight the ERK/FoxO3a axis as a potential regulatory pathway involved in AP pathology and a possible therapeutic target.