A Lipid Perspective on Regulated Pyroptosis

Abstract

Pyroptosis is a novel pro-inflammatory cell programmed death dependent on Gasdermin (GSMD) family-mediated membrane pore formation and subsequent cell lysis, accompanied by the release of inflammatory factors and expanding inflammation in multiple tissues. All of these processes have impacts on a variety of metabolic disorders. Dysregulation of lipid metabolism is one of the most prominent metabolic alterations in many diseases, including the liver, cardiovascular system, and autoimmune diseases. Lipid metabolism produces many bioactive lipid molecules, which are important triggers and endogenous regulators of pyroptosis. Bioactive lipid molecules promote pyroptosis through intrinsic pathways involving reactive oxygen species (ROS) production, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, lysosomal disruption, and the expression of related molecules. Pyroptosis can also be regulated during the processes of lipid metabolism, including lipid uptake and transport, de novo synthesis, lipid storage, and lipid peroxidation. Taken together, understanding the correlation between lipid molecules such as cholesterol and fatty acids and pyroptosis during metabolic processes can help to gain insight into the pathogenesis of many diseases and develop effective strategies from the perspective of pyroptosis.

A natural hydrogel complex improves intervertebral disc degeneration by correcting fatty acid metabolism and inhibiting nucleus pulposus cell pyroptosis

“…It is worth noting that lipid metabolism plays a crucial role in the generation of various bioactive lipid molecules, which serve as pivotal initiators and intrinsic regulators of pyroptosis. These bioactive lipid molecules have been found to facilitate pyroptosis by disrupting the intrinsic pathways involved in the production of ROS, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, lysosomal disruption, and expression of associated molecules [ 58 ]. Recent research has demonstrated that the activation of NLRP3 inflammasome can induce lipid accumulation and pyroptosis in hepatocytes through the stimulation of free fatty acids [ 59 ].…”

ROS induced pyroptosis in inflammatory disease and cancer

“…External stimulus causing incomplete or incorrect protein folding in the ER leads to ER stress ( 134 ). Continuous or strong ER stress activates signaling pathways that result in cell damage or death ( 135 ). Recent reports indicate that ER stress is closely related to cell pyroptosis.…”

ACSL4-Mediated Ferroptosis and Its Potential Role in Central Nervous System Diseases and Injuries

“…In general, ferroptosis has three essential features: (1) oxidation of PUFAs (including membrane phospholipids); (2) redox activities related to iron utilization; (3) loss of lipid hydrogen peroxide (LOOH) repair capacity [ 8 ]. Morphologically, ferroptosis cells exhibit typical changes in mitochondrial membrane shrinkage, reduction or disappearance of mitochondrial cristae, and rupture of the outer membrane, whereas mitochondria usually show swelling in other forms of cell death [ 39 , 40 , 41 ]. Furthermore, treated with the ferroptosis inducer erastin, the nuclei of cancer cells retained their structural integrity and no nuclear pyknosis or chromatin edge clustering was observed [ 42 ].…”