CD36 Induces Inflammation by Promoting Ferroptosis in Pancreas, Epididymal Adipose Tissue, and Adipose Tissue Macrophages in Obesity-Related Severe Acute Pancreatitis.

Severe acute pancreatitis (SAP) is mainly triggered by the abnormal activation of pancreatic enzymes. Obesity acts as an independent risk factor for SAP; however, the underlying mechanism has not been fully elucidated. In this study, SAP models were established in mice with normal and high-fat diets. Subsequently, this study examined ferroptosis and inflammatory markers in pancreas and epididymal adipose tissues. To mimic obesity-related SAP in adipose tissue macrophages (ATMs), lipopolysaccharide (LPS) and palmitic acid (PA) were introduced, and alterations in ferroptosis and inflammation were assessed. To elucidate the regulatory role of cluster of differentiation 36 (CD36) in ferroptosis, liproxstatin-1 (Lip-1) and sulfosuccinimidyl oleate sodium (SSO) were utilized for in-depth analysis in the pancreas, epididymal adipose tissues, and ATMs. Our findings suggest that obesity aggravates ferroptosis in pancreas tissue, epididymal adipose tissues, and ATMs during SAP, as evidenced by increased lipid peroxidation, elevated Fe(2+) levels, and alterations in ferroptosis markers, while these alterations were regained by Lip-1. Notably, CD36 levels were significantly increased in pancreatic tissue, epididymal adipose tissue, and ATMs, indicating that CD36 promotes ferroptosis and induces inflammation. SSO treatment alleviated changes in ferroptosis markers and reduced inflammation. Western blot results showed that CD36 promoted ferroptosis through the acyl-CoA synthetase long-chain family member 4 (ACSL4)/glutathione peroxidase 4 (GPX4) axis in pancreatic tissue, while a similar regulatory role was mediated by the ferritin heavy chain 1 (FTH1)/GPX4 axis and ATMs. These findings demonstrate that CD36 induces inflammation by facilitating ferroptosis in pancreas tissue, epididymal adipose tissue, and ATMs in obesity-related SAP. The inhibition of CD36 could provide novel viewpoints for the prevention and treatment of obesity-related SAP.