Baicalin Attenuates Chronic Pancreatitis through SIRT5-Mediated Nrf2 Deacetylation and JAK-STAT Pathway Modulation: Implications for Natural Product-Based Therapy

Chronic pancreatitis (CP) is a progressive inflammatory disease marked by irreversible pancreatic fibrosis and functional decline, for which effective treatments are relatively scarce. This study explores the protective role of the dietary flavonoid baicalin (BA) in CP, with emphasis on its modulation of Sirtuin 5 (SIRT5) and associated signaling cascades. Through bioinformatics screening, nuclear factor erythroid 2-related factor 2 (Nrf2) was identified as a pivotal factor in CP pathogenesis. In rat pancreatic ductal epithelial cells (RPDECs), BA administration or Nrf2 knockdown promoted cell proliferation, inhibited apoptosis, suppressed pro-inflammatory cytokines, and facilitated Th2 polarization. In a CP rat model, BA alleviated fibrosis, reduced neutrophil accumulation, and limited collagen deposition, alongside a decline in serum levels of amylase, lipase, and trypsin. Mechanistically, multi-omics analysis demonstrated that BA activated SIRT5, leading to Nrf2 deacetylation and subsequent suppression of the JAK-STAT axis. This regulatory effect rebalanced immune responses by limiting Th1/Th17-mediated inflammation and enhancing Th2/Treg activity, thereby reducing pancreatic injury. Collectively, our findings suggest that BA mitigates CP through SIRT5/Nrf2-driven modulation of immune-fibrotic interactions, supporting its potential as a dietary agent for targeted inflammation and fibrosis control in CP.