Cell death includes programmed and nonprogrammed cell death. The former mainly includes ferroptosis, necroptosis, pyroptosis, autophagy, and apoptosis, while the latter refers to necrosis. Accumulating evidence shows that ferroptosis, necroptosis, and pyroptosis play essential regulatory roles in the development of intestinal diseases. In recent years, the incidence of inflammatory bowel disease (IBD), colorectal cancer (CRC), and intestinal injury induced by intestinal ischemia–reperfusion (I/R), sepsis, and radiation have gradually increased, posing a significant threat to human health. The advancement in targeted therapies for intestinal diseases based on ferroptosis, necroptosis, and pyroptosis provides new strategies for treating intestinal diseases. Herein, we review ferroptosis, necroptosis, and pyroptosis with respect to intestinal disease regulation and highlight the underlying molecular mechanisms for potential therapeutic applications.

In recent years, three emerging cell deaths, ferroptosis, necroptosis and pyroptosis, have gradually attracted everyone’s attention, and they also play an important role in the occurrence and development of various diseases. Ferroptosis is an idiographic iron-dependent form regulated cell death with the hallmark of accumulation of the intracellular reactive oxygen species (ROS). Necroptosis is a form of regulated necrotic cell death mediated by the receptor-interacting protein kinase 1(RIPK1) and receptor-interacting protein kinase 3RIPK3. Pyroptosis, also known as cell inflammatory necrosis, is a programmed cell necrosis mediated by Gasdermin D (GSDMD). It is manifested by the continuous swelling of the cells until the cell membrane ruptures, resulting in the release of the cell contents and the activation of a strong inflammatory response. Neurological disorders remain a clinical challenge and patients do not respond well to conventional treatments. Nerve cell death can aggravate the occurrence and development of neurological diseases. This article reviews the specific mechanisms of these three types of cell death and their relationship with neurological diseases and the evidence for the role of the three types of cell death in neurological diseases; understanding these pathways and their mechanisms is helpful for the treatment of neurological diseases.

Intestinal ischemia/reperfusion (I/R), which is associated with high morbidity and mortality, is also accompanied with abnormal energy metabolism and liver injury. Irisin, a novel exercise-induced hormone, can regulate adipose browning and thermogenesis. The following study investigated the potential role of dexmedetomidine in liver injury during intestinal I/R in rats. Adult male Sprague–Dawley rats underwent occlusion of the superior mesenteric artery for 90 min followed by 2 h of reperfusion. Dexmedetomidine or irisin-neutralizing antibody was intravenously administered for 1 h before surgery. The results demonstrated that severe intestine and liver injuries occurred during intestinal I/R as evidenced by pathological scores and an apparent increase in serum diamine oxidase (DAO), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) levels. In addition, the hepatic irisin, cleaved caspase-3, Bax, and NLRP3 inflammasome components (including NLRP3, ASC, and caspase-1), protein expressions, apoptotic index, reactive oxygen species (ROS), malondialdehyde (MDA), myeloperoxidase (MPO), tumor necrosis factor- (TNF-) α, and interleukin- (IL-) 6 levels increased; however, the serum irisin level and hepatic Bcl-2 protein expression and superoxide dismutase (SOD) activity decreased after intestinal I/R. Interestingly, dexmedetomidine could reduce the above listed changes and increase the irisin levels in plasma and the liver in I/R rats. Dexmedetomidine-mediated protective effects on liver injury and NLRP3 inflammasome activation during intestinal I/R were partially abrogated via irisin-neutralizing antibody treatment. The results suggest that irisin might contribute to the hepatoprotection of dexmedetomidine during intestinal ischemia/reperfusion.

Ischemia-reperfusion injury (IRI) is a critical condition that poses a significant threat to patient safety. The production of lactate increases during the process of IRI, and lactate serves as a crucial indicator for assessing the severity of such injury. Lactylation, a newly discovered post-translational modification in 2019, is induced by lactic acid and predominantly occurs on lysine residues of histone or nonhistone proteins. Extensive studies have demonstrated the pivotal role of lactylation in the pathogenesis and progression of various diseases, including melanoma, myocardial infarction, hepatocellular carcinoma, Alzheimer’s disease, and nonalcoholic fatty liver disease. Additionally, a marked correlation between lactylation and inflammation has been observed. This article provides a comprehensive review of the mechanism underlying lactylation in IRI to establish a theoretical foundation for better understanding the interplay between lactylation and IRI.