Chaihu Shugan Powder Attenuates Ferroptosis-Associated Injury in Acute Pancreatitis by Activating PGC-1α/Nrf2/HO-1 Pathway.

Abstract

Acute pancreatitis (AP) is a life-threatening condition driven by premature pancreatic enzyme activation, leading to systemic complications and multi-organ dysfunction. Chaihu Shugan Powder (CSP) has been reported to mitigate pancreatic injury associated with AP, but the detailed regulatory mechanism was unclear. In our study, we investigated the fundamental mechanism of how CSP attenuated AP injury. The AP models were constructed by applying cerulein in AR42J cells and rats. Individual CSP interventions did not affect normal cell function. CSP partially reversed cerulein-induced cell damage, as reflected by increased cell viability, the level of glutathione (GSH), and ferroptosis protein markers but decreased the contents of inflammatory factor, reactive oxygen species (ROS), malondialdehyde (MDA), Fe²⁺ and iron. CSP activated the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α)/nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway, which in turn reduced ferroptosis in cerulein-exposed AR42J cells. Silencing the PGC-1α gene could partially inhibit the activation of the PGC-1α/Nrf2/HO-1 pathway by CSP in cerulein-induced AR42J cells. In AP rats, CSP alleviated AP-related pathomorphological changes and ferroptosis in rats by activating PGC-1α/Nrf2/HO-1 pathway. Altogether, the mechanism by which CSP alleviated AP injury in rats may be correlated with the activation of PGC-1α/Nrf2/HO-1 pathway.