A novel role of E2F transcription factor 1 in pancreatic stellate cell activation through polyamine metabolism modulation.

Activated pancreatic stellate cells (PSCs) drive pancreatic fibrosis. The transcription factor E2F1 has been implicated in various cellular processes, but its specific role and regulatory mechanisms in PSC activation and pancreatic fibrosis remain unclear. This study aimed to investigate these aspects and evaluate the therapeutic potential of Chidamide for pancreatic fibrosis. In this study, single-cell transcriptomic analysis of a chronic pancreatitis (CP) model revealed that the HDAC1 signaling pathway, which acts as an upstream negative regulator of E2F1, is significantly dysregulated in PSCs. Functional experiments demonstrated that E2F1 effectively suppresses PSC activation, migration, and invasion. Mechanistically, E2F1 directly binds to and transcriptionally activates PIWIL1. Subsequently, PIWIL1 downregulates the expression of the rate-limiting polyamine metabolic enzymes ODC and SRM, thereby modulating the PSC phenotype. Key functional rescue experiments confirmed that inhibiting polyamine synthesis recapitulated the anti-fibrotic phenotype observed with PIWIL1 overexpression, whereas exogenous polyamine supplementation reversed this phenotype. These findings establish polyamine metabolism as the core effector node of this regulatory axis. Upstream investigations further revealed that E2F1 activity is modulated by HDAC1-mediated deacetylation, and treatment with Chidamide induced the level of E2F1 in acetylated antibody-precipitated complexes. Furthermore, Chidamide significantly elevated desmin, PIWIL1, and E2F1 in PSCs, while reducing ODC/SRM, thereby alleviating pancreatic fibrosis. In summary, this study elucidates that E2F1 inhibits PSC activation via PIWIL1/polyamine metabolic pathway, regulated by HDAC1. Targeting HDAC1 with Chidamide restores E2F1 function, suggesting a promising therapeutic strategy for pancreatic fibrosis.