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.

Keywords: NLRP3; inflammasome.; lipid metabolism; lipids; pyroptosis.

Figure 1

The timeline of pyroptosis

Figure 2

Regulation of lipid metabolism in pyroptosis. A Lipid synthesis and pyroptosis. Enzymes in cholesterol and fatty acid biosynthesis, including FASN and HMGCR can promote the occurrence and development of pyroptosis. In addition, the pyroptosis-related protein caspase-4 promote critical enzymes in fatty acid synthesis, including ACC and FASN. B Lipid uptake and transport with pyroptosis. LDLR and ABCA1 restrain NLRP3 inflammasome activation and prevent caspase-1 cleaving GSDMD to promote the release of the N-terminal domain, which executes pores formation and pyroptosis. The combination of FABP4 and MUFA can reduce activation of SIRT1 and acetylation of p53, promoting NLRP3-dependent pyroptosis. C Lipid storage and pyroptosis. Hypertrophic adipocytes can induce NLRP3-dependent caspase-1 activation and pyroptosis, and obese adipocytes also regulate the secretion of APN and leptin. APN and leptin promote pyroptosis via FoxO4 or ROS production/ER stress/autophagy induction/cathepsin B maturation axis respectively. D Lipid peroxidation and pyroptosis. GPX4 and ALOX5 inhibit or promote lipid peroxidation respectively, leading to caspase-11-dependent pyroptosis. Lipid peroxidation triggers NLRP3 inflammasome and caspase-1 activation by inducing PLC γ1 activation.