Ferroptosis: potential targets and emerging roles in pancreatic diseases

Abstract

Ferroptosis is a newly discovered form of regulatory cell death characterized by excessive iron-dependent lipid peroxidation. In the past decade, significant breakthroughs have been made in comprehending the features and regulatory mechanisms of ferroptosis, and it has been confirmed that ferroptosis plays a pivotal role in the pathophysiological processes of various diseases, including tumors, inflammation, neurodegenerative diseases, and infectious diseases. The pancreas, which is the second largest digestive gland in the human body and has both endocrine and exocrine functions, is a vital organ for controlling digestion and metabolism. In recent years, numerous studies have confirmed that ferroptosis is closely related to pancreatic diseases, which is attributed to abnormal iron accumulation, as an essential biochemical feature of ferroptosis, is often present in the pathological processes of various pancreatic exocrine and endocrine diseases and the vulnerability of the pancreas to oxidative stress stimulation and damage. Therefore, comprehending the regulatory mechanism of ferroptosis in pancreatic diseases may provide valuable new insights into treatment strategies. In this review, we first summarize the hallmark features of ferroptosis and then analyze the exact mechanisms by which ferroptosis is precisely regulated at multiple levels and links, including iron metabolism, lipid metabolism, the GPX4-mediated ferroptosis defense system, the GPX4-independent ferroptosis defense system, and the regulation of autophagy on ferroptosis. Finally, we discuss the role of ferroptosis in the occurrence and development of pancreatic diseases and summarize the feasibility and limitations of ferroptosis as a therapeutic target for pancreatic diseases.

Keywords: Acute pancreatitis; Diabetes mellitus; Ferroptosis; Pancreatic ductal adenocarcinoma; Regulated cell death.