SCD1 protects acinar cells from ferroptosis during severe acute pancreatitis by balancing lipid and redox homeostasis

During severe acute pancreatitis (SAP), the circulating free fatty acid levels are elevated, and this elevation correlates with a poor prognosis. However, the precise mechanisms by which lipid metabolism influences the progression of SAP remain unclear. Considering that stearoyl-CoA desaturase (SCD1) is a key lipid-modifying enzyme, we investigated its role in SAP. Using caerulein and ligation-induced SAP models along with RNA Sequencing, we found that SCD1 is upregulated in SAP models. Through studies with Scd1 knockout mice and acinar cells, we determined that the absence of SCD1 exacerbates pathological damage and inflammatory responses in SAP model mice while inducing lipid peroxidation and Ferroptosis. By employing Sirt^-/- mice and a lipid metabolomic analysis, we found that SIRT1 upregulates SCD1 expression through deacetylation, thereby contributing to Ferroptosis resistance by altering the fatty acid composition. By examining the effects of monounsaturated fatty acids (palmitoleic acid) on SCD1 siRNA-transfected cells, we observed that MUFAs can counteract lipid peroxidation and promote SIRT1 expression, forming a positive feedback loop that resists Ferroptosis in SAP model mice. Our findings indicate that SCD1-mediated cellular lipid and redox homeostasis plays a key role in SAP defense, suggesting a potential mechanism for SAP prevention and treatment.

Fatty acid metabolism; Ferroptosis; Oxidative stress; SCD1; Severe acute pancreatitis.