Targeting ferroptosis mediated cell death: a novel strategy for mitigating acute pancreatitis.

Acute pancreatitis (AP) is a common and potentially fatal inflammatory disorder characterized by pancreatic tissue inflammation and necrosis. Though our understanding of its pathogenesis has advanced, effective therapeutic approaches remain elusive, with many potential strategies still unexplored. Ferroptosis, an iron-dependent form of regulated cell death marked by the accumulation of lipid peroxides, plays a crucial role in tissue damage and inflammation. It has been implicated in various disorders, including neurodegenerative diseases like Alzheimer and Parkinson, ischemia-reperfusion injury, cancer, and other metabolic diseases. In AP, ferroptosis exacerbates disease progression by promoting pancreatic inflammation and cellular damage, thereby worsening clinical outcomes. However, its role in AP remains insufficiently explored due to the complexity of its molecular mechanisms and the limited availability of targeted interventions. This comprehensive review summarizes the factors involved in ferroptosis, such as glutathione depletion, defective lipid peroxide detoxification, dysregulation of iron homeostasis, and discusses established and emerging biomarkers. Furthermore, we discuss the FDA approved drugs and other investigational compounds targeting ferroptosis, along with the role of pro-inflammatory mediators, lipid peroxidation products, glutathione peroxidase 4 (GPX4), and iron regulatory proteins. The influence of PAMPs and DAMPs on ferroptosis signaling along with the potential role of epigenetic regulation is also highlighted. Overall, this review provides an integrated perspective on the role of ferroptosis in AP and emphasizes its potential as a novel therapeutic approach to mitigate AP. The goal is to use these insights into clinical practice to reduce the burden of this difficult condition.