Pyroptosis is a type of programmed cell death that is involved in host defense against microbial infections and the regulation of inflammatory responses. This process is characterized by the formation of plasma membrane pores, which leads to the release of pro-inflammatory cytokines and amplification of immune responses. Recent research has revealed that protein palmitoylation, a reversible lipid modification, plays a significant role in the regulation of pyroptotic pathways. Understanding the interplay between pyroptosis and palmitoylation provides insights into the complex mechanisms governing innate immunity and disease pathogenesis.

Protein palmitoylation involves the attachment of palmitate, a 16-carbon saturated fatty acid, to cysteine residues of target proteins. This lipid modification is implicated in diverse cellular processes, including signal transduction, protein trafficking, and membrane localization. Palmitoylation is regulated by palmitoyl acyltransferases (PATs), which contain a conserved zinc finger DHHC motif (Asp-His-His-Cys). In humans, there are 23 identified enzymes of ZDHHC-PATs, named ZDHHC1 to ZDHHC24, excluding ZDHHC10 [1]. Recent studies have highlighted the involvement of palmitoylation in the regulation of various pyroptosis-associated proteins, such as cyclic GMP-AMP synthase (cGAS), nucleotide-binding domain and leucine-rich repeat-containing protein 3 (NLRP3), stimulator of interferon genes (STING), gasdermin D (GSDMD), and gasdermin E (GSDME).

The cGAS-STING pathway is an essential sensor for detecting cytosolic DNA and initiating downstream immune signaling pathways. As a member of the cGAS-STING signaling axis, cGAS responds to pathogens or damaged DNA to trigger an innate immune reaction [2]. cGAS is defined as a pattern-recognition receptor (PRR) that plays a critical role in recognizing and binding to cytosolic double-stranded DNA [3]. STING, also known as MPYS (designated based on its N-terminal methionine-proline-tyrosine-serine amino acid sequence), endoplasmic reticulum IFN stimulator (ERIS), mediator of interferon regulatory factor 3 (IRF3) activation (MITA), and transmembrane protein 173 (TMEM173), was initially identified as a transducer of death signals from major histocompatibility complex class II molecules. It plays a crucial role in inducing the production of type I interferons in response to infection. Additionally, STING is involved in regulating programmed cell death, including pyroptosis, autophagy, necroptosis, and ferroptosis, in various diseases such as CNS injury, cardiac dysfunction, and hepatic disease.

The NLRP3 inflammasome is a crucial component of the intracellular defense system, responsible for sensing potential threats and initiating immune responses. It consists of three main components: NLRP3, caspase-1, and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) [4]. When activated, the NLRP3 inflammasome triggers the activation of caspase-1, which in turn promotes the maturation of pro-IL-1β and pro-IL-18 [5]. These cytokines play a vital role in initiating inflammation, attracting innate immune cells, and influencing subsequent adaptive immune responses [6].

The gasdermins (GSDM) are a family of pore-forming effector proteins that play a vital role in pyroptosis, a programmed inflammatory cell death controlled by the release of pro-inflammatory cytokines and alarmins. Pyroptosis is an essential process in inflammation and host defense responses [7], [8]. The GSDM family consists of six paralogous genes in humans: GSDMA, GSDMB, GSDMC, GSDMD, GSDME (also named deafness associated tumor suppressor 5, DFNA5), andPejvakin (PJVK) (also named autosomal recessive deafness type 59 protein, DFNB59) [1]. Except for DFNB59, all the GSDM family proteins play multiple roles in pyroptosis.

The nucleotide-binding oligomerization domain (NOD) proteins NOD1 and NOD2, members of the evolutionarily conserved NOD-like receptor (NLR) family, are crucial in innate immune responses against specific bacterial infections [9]. NOD1 and NOD2 consist of three main parts: a C-terminal sequence of leucine-rich repeats (LRRs), a central nucleotide-binding domain (NBD; also known as NOD domain), and an N-terminal caspase recruitment domain (CARD). Unlike NOD1, which contains a single CARD, NOD2 has two CARDs at its N-terminal [10]. The primary function of NOD1 and NOD2 is to identify internal components of bacterial peptidoglycan, leading to the activation of proinflammatory cytokines and antimicrobial substances [11]. Additionally, NOD1 and NOD2 have been implicated in pyroptosis [12], [13].

Recent studies have provided evidence that palmitoylation plays a regulatory role in pyroptosis, forming a novel regulatory axis in innate immunity. The interplay between pyroptosis and palmitoylation is involved in the precise control of immune responses and inflammation. Various proteins, including cGAS, NLRP3, STING, GSDMD, GSDME, NOD1, and NOD2, undergo palmitoylation-mediated regulation, contributing to the fine-tuning of immune responses and inflammation control. This review aims to explore the current understanding of the role of protein palmitoylation in pyroptotic pathways, shedding light on the underlying mechanisms and potential therapeutic opportunities for manipulating immune responses and treating inflammatory diseases. By comprehending the intricate interplay between pyroptosis and palmitoylation, novel therapeutic targets within the field of immunology may be revealed.