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. 2025 Feb 27;18(1):110–123. doi: 10.1016/j.chmed.2025.02.009

Protein S-acylation: Pathological mechanisms and novel therapeutic targets for diabetic complications

Ruiting Liu a,b,1, Nuo Xu a,b,1, Xuejiao Song a,b, Yanying Li a,b, Jie Bu a,b, Runtao Su a,b, Hong Guo a,b, Chen Jiang c,d, Pengwei Zhuang a,b,c,d, Yanjun Zhang a,b,c,d,⁎, Qingsheng Yin a,b,⁎
PMCID: PMC12828149  PMID: 41584711

Abstract

Diabetes involves multi-organ complications that seriously threaten human life and health, and has become a major public health problem of global concern. Unfortunately, clinical management strategies for diabetic complications are still in their “infancy”, restricted by a limited understanding of their complex pathological mechanism. As is well established, lipid metabolism disorder is the characteristic pathological factors of diabetes, but the detailed molecular mechanisms driving the progression of multi-organ complications remain obscure. Protein S-acylation (often referred to as S-palmitoylation) is a reversible lipid modification that reversibly binds fatty acids to protein-specific cysteine (Cys) residues through palmitoyl acyl transferases (PATs, also known as DHHCs) and deacylation enzymes, which is involved in the pathological progression of a variety of complex diseases such as cancer, neurological disorders and metabolic syndrome. Notably, recent studies have shown that protein S-acylation drives the progression of diabetes and its multiple complications, and targeted intervention in the protein S-acylation process significantly alleviates the progression of diabetes and its complications, suggesting that protein S-acylation may be a common pathological link and intervention target of diabetes complications. Therefore, this review systematically comprehends the contribution of protein S-acylation to the progression of diabetes and its complications, summarizes the influence of the diabetic environment on S-acylation related enzymes, as well as providing an in-depth analysis of current drugs, measures, and challenges in targeting S-acylation. Finally, the accessibility of targeting protein S-acylation to prevent diabetes and its complications and the focus of future in-depth studies are envisioned, with a view to providing comprehensive and in-depth references and rationale for future novel strategies targeting protein S-acylation to prevent and treat diabetes and its multi-organ complications.

Keywords: diabetes, diabetic complications, S-acylation, S-palmitoylation, targeted therapy

1. Introduction

Diabetes is a chronic metabolic disease characterized by hyperglycemia, the incidence of which is increasing with each passing year, and has become one of the major chronic diseases affecting health of people all over the world (Li et al., 2019, Maresch et al., 2018). According to the Global Diabetes Map report released by the International Diabetes Federation (IDF) in 2021, about 537 million adults worldwide have diabetes, and this number is expected to surge to 783 million by 2045 (Magliano, Boyko, & IDF Diabetes Atlas 10th edition scientific committee, 2021). At present, with the increase in the number of people with diabetes and the advent of an aging society, people have gradually realized that the multi-organ complications involved in diabetes are the real “killer” threatening the life and health of diabetic patients and the elderly (Es et al., 2014). Clinical studies have shown that when the course of diabetes exceeds five years, the risk of complications will rise sharply, which will seriously affect the health of patients and causing a huge economic burden to families and society (Zoungas et al., 2014). Among 35.3 million patients with type 2 diabetes mellitus (T2DM), about 21.3% were found to be complicated with relatively serious chronic kidney disease, showing a rapid growth trend (Zhang et al., 2016). The prevention and treatment of diabetes-induced chronic complications has gradually became a key task in the current healthcare community, and its strategy has also changed from “centering on blood sugar control” to “aiming at improving cardiac and renal outcomes” (American Diabetes Association Professional Practice Committee, 2024). Unfortunately, unlike the phased progress made in the prevention and treatment of diabetes, the current understanding of diabetes complications is still in the initial stage, and the clinical prevention and treatment effect is unsatisfactory. Therefore, revealing the key pathological mechanism of diabetes-induced complications can provide a new strategy for their prevention and treatment.

Notoriously, lipid metabolism disorder is one of the characteristic pathological factors of diabetes, which can participate in the pathological progression of diabetic complications by mediating multi-organ damage through multicellular signaling (Eid et al., 2019). Accumulated clinical and preclinical studies have also found that the target organs involved in diabetes are associated with fatty acid accumulation. Excess lipid accumulation in cardiomyocytes has been found in the hearts of patients with T2DM, and this lipid accumulation is associated with decreased cardiac systolic or diastolic function (Goldberg, Trent, & Schulze, 2012). Preclinical studies have also shown that bulk fatty acids such as palmitic acid, oleic acid and stearic acid are accumulated in the hippocampal and renal tubular cells of high-fat diet (HFD) mice, and these fatty acids are closely related to cognitive damage and the progression of kidney disease (Pérez-Martí et al., 2022, Spinelli et al., 2017). Unfortunately, the detailed pathways by which fatty acid multiorgan accumulation induced by lipid metabolism disorder drives the pathological progression of diabetic complications remain obscure.

S-acylation is a common protein lipid modification, which is a reversible lipid modification mediated by PATs and deacylation enzymes that covalently binds palmitoyl-coenzyme A derived from palmitic acid to the cysteine (Cys) residue of protein through the sulfolipid bond (Linder & Deschenes, 2007). Accumulating studies have shown that protein S-acylation is involved in the progression of various diseases such as cancer, neurological disorders, metabolic syndrome, infection (Globa and Bamji, 2017, Ko and Dixon, 2018, Sobocińska et al., 2018). Since the diabetic state is accompanied by abnormal accumulation of fatty acids, numerous recent studies have gradually found that protein S-acylation is involved in the development of diabetes and mediates the progression of diabetic complications. Studies have shown that S-acylation is associated with metabolic dysregulation of pancreatic β-cells (Wu et al., 2021). A study by Dong et al. also found that the absence of deacylation enzymes APT1 in pancreas promoted the hypersecretion of insulin and pancreatic β-cells failure in db/db mice (Dong et al., 2023). Moreover, it has been shown that S-acylation of the fatty acid transporter protein CD36 can lead to diabetic myocardial dysfunction by increasing lipid accumulation in cardiomyocytes (Wang et al., 2024). Some studies have found that the S-acylation of CD36 is also found in diabetic kidney disease (DKD), which aggravates renal fibrosis by promoting the mesenchymal transdifferentiation of renal tubular epithelial cells and aggravating renal inflammatory infiltration, while inhibition of CD36 S-acylation by using 2-bromopalmitate (2-BP) has been found to alleviate renal injury in studies (Feng, 2018, Xiao, 2017). These evidences suggest that protein S-acylation may be an important bridge between metabolic disorders and tissue damage in diabetes, and targeting protein S-acylation may be a novel strategy to prevent and treat diabetic complications. Therefore, this review focuses on the intrinsic relationship between protein S-acylation and diabetes and its complications, systematically reviews the contribution of protein S-acylation to the progression of diabetes and its induced chronic complications, and summarizes the effects of the diabetic environment on S-acylation related enzymes. The potential drugs, strategies and challenges of targeting S-acylation for the treatment of the disease are also discussed in depth, and finally, the accessibility of targeting S-acylation for the prevention and treatment of diabetes and its complications and the focus of future in-depth studies are foreseen, with a view to providing comprehensive and in-depth references and bases for the new strategies of targeting protein S-acylation for the prevention and treatment of diabetes and its multiorgan complications.

2. S-acylation

S-acylation is an important lipid modification that regulates protein localization, accumulation, secretion and function by altering the affinity of proteins to membranes (Jiang et al., 2018). There are three types of acylation: S-acylation, N-acylation and O-acylation. N-acylation occurs when a fatty acid palmitate is linked to Cys at the N-terminal of a protein by a stable amide bond, while O-acylation refers to a palmitoylation process in which the monounsaturated form of palmitate (cis Δ9 palmitate) binds to the hydroxyl group of serine or threonine by an oxyester linkage (Liu et al., 2022). S-acylation is the process by which a fatty acid is covalently bound to a specific Cys residue of a protein via an unstable thioester bond (Malgapo and Linder, 2021). Of these, S-acylation is the main modification type (Liu et al., 2022). S-acylation is a tightly regulated reversible cyclic process catalyzed by PATs, while deacylation enzymes take care of the deacylation process (De and Sadhukhan, 2018, Iwanaga et al., 2009, Won and Martin, 2018).

At present, known PATs mainly include members of the zinc finger DHHC (zDHHC) palmitoacylase family (Nadolski and Linder, 2007, Zhou et al., 2023). zDHHC family proteins are named because they all contain the conserved DHHC (Asp-His-His-Cys) enzyme activity domain. In mammals, zDHHCs consist 23 members: zDHHC1−24 (skipping zDHHC10), which catalyze the protein S-acylation reaction (Liu et al., 2020). Most zDHHC enzymes are located in the Golgi apparatus and endoplasmic reticulum (ER), which are the main sites for S-acylation of proteins in mammalian cells (Runkle et al., 2016). Only a few PATs such as zDHHC5, zDHHC20 and zDHHC21 are localized in the plasma membrane, mitochondria and perinuclear regions (Rocks et al., 2010, Runkle et al., 2016). The localisation of DHHC-PATs partly depends on structure and motif, for example lysine-based sorting signals on the sequences of DHHC4 and DHHC6 enable them to form KXX and KKXX motifs, thus guiding them to the ER membrane (Gorleku, Barns, Prescott, Greaves, & Chamberlain, 2011). Many studies have shown that zDHHC can catalyze the protein S-acylation, but the exact process is unknown. Previous studies have identified that some zDHHCs catalyze S-acylation of substrates through a two-step (ping-pong) mechanism (Roth, Feng, Chen, & Davis, 2002). First, zDHHC undergoes the process of auto-acylation, in which Cys at the active site carries out nucleophilic attack on the carbonyl thioester of palmitoyl-CoA to form acyl-enzyme intermediates connecting palmitoyl-CoA to the DHHC domain. This intermediate then transfers the palmitoyl group to the Cys of the substrate, thus completing S-acylation (Jennings and Linder, 2012, Rana et al., 2018).

The number of deacylation enzymes is much smaller than that of PATs, and the reported deacylation enzymes are mainly classified into three groups: Acyl protein thioesterases (APT), palmitoyl protein thioesterases (PPT) and alpha beta hydrolase domain (ABHD) deacylation (Won, Cheung & Martin, 2018). APT includes APT1/2, but APT2 and APT1 are located differently in the cell. Although these enzymes share approximately 60% identity, studies suggest that there are preferences for specific palmitoylated substrates between APT1 and APT2. For example, the deacylation of zDHHC6 depends on APT2 rather than APT1 (Abrami et al., 2017). In addition to cytosolic APTs, another class of enzymes PPTs (PPT1 and PPT2) localise in lysosomes. Normally, PPT1 facilitates the degradation of substrate proteins by depalmitoylating them in the lysosomes (Yuan et al., 2021). Similar to APT1/2, PPT1 and PPT2 have similar structural characteristics as homologous lysosomal thioesterases, but the conformational differences near the active site partially explain substrate selectivity, as the entrance space of the lipid binding site consisting of β3-αA and β8-αF in PPT1 is larger than that in PPT2 and thus more inclusive of the substrates, which may participate in the deacylation of more substrates (Calero et al., 2003). ABHDs including ABHD10, ABHD12 and ABHD17A/B/C have been identified as another category of cytosolic deacylation enzymes (Remsberg et al., 2021, Won et al., 2018). However, there are limited studies on the deacylation enzymes activity, substrate-binding structure characteristics, substrate preferences and other physiological roles of ABHD family proteins, and further research is needed to determine the specific contribution of ABHDs family proteins in the process of depalmitoylation. To summarize, the two enzymes, PATs and deacylation enzymes, together maintain the protein S-acylation cycle and are indispensable in the regulation of protein function and intracellular signal transduction.

In addition to performing essential physiological functions, there is growing evidence that protein S-acylation is strongly associated with the progression of a variety of diseases, including cancer and neurodegenerative diseases (Pan & Chen, 2022). Notably, the recent accumulation of studies also suggests that S-acylation is involved in the pathological progression of metabolic diseases such as non-alcoholic fatty liver disease (NAFLD), obesity, hyperlipidemia, and diabetes (Dong et al., 2023, Zheng et al., 2024). Given that disorders of lipid metabolism as well as fatty acid accumulation are common pathological mechanisms factors in diabetes and its induced multi-organ complications, emerging studies have also gradually focused on the involvement of protein S-acylation in the progression of diabetes-induced multi-organ complications. Thus, in the following, the contribution and mechanisms of protein S-acylation in the progression of diabetes and its complications are elaborated, with a view to providing a theoretical basis for targeting S-acylation to prevent diabetes and its complications.

3. S-acylation drives molecular mechanisms of T2DM

T2DM, which is mainly characterized by the failure of pancreatic β-cells due to lipid accumulation and insufficient glucose uptake by target organs due to insulin resistance, is now one of the major chronic diseases affecting the health of people worldwide (Chatterjee, Khunti, & Davies, 2017). More than 1.31 billion people are expected to have diabetes globally by 2050, with the overall age-standardized prevalence of diabetes projected to increase from 6.1% in 2021 to 9.8% (GBD 2021 Diabetes Collaborators., 2023). However, due to the vague understanding of the complex pathological mechanism of T2DM, the current prevention and treatment effect is not good, and further research is needed to clarify its pathogenesis.

It is well known that dysfunction of pancreatic β-cell is a key factor in the pathological process of T2DM. Recent studies have found that high glucose treatment of normal pancreatic can reduce the APT1 enzyme activity in β-cells, and it has also been found that after APT1 is knocked down in normal pancreas, glucose stimulation can significantly increase insulin secretion, suggesting that APT1 can inhibit insulin secretion. Based on this, further exploration revealed that knockout of APT1 can increase the S-acylation level of secretory carrier membrane protein 1 (Scamp1), which leaded to delayed closure of insulin vesicular fusion pores in β-cell membranes, resulting in insulin hypersecretion, and significantly reduced area of β-cell in the later stages of diabetes. It was confirmed that impaired deacylation of Scamp1 is closely association with the failure of β-cells. Additionally, since APT1 and APT2 are homologous acyl protein thioesterases, the researchers further investigated whether APT2 knockout mice had a similar phenomenon, and they found that APT2 knockout mice had no effect on either glucose tolerance or insulin levels, indicating the specificity of APT1 in this process (Dong et al., 2023). These findings suggest that a decrease in specific APT1 activity in β-cells may promote the progression of T2DM.

Glucose transporter type 4 (GLUT4) is another important regulator in glucose transport and metabolic homeostasis, and GLUT4 dysfunction causes hyperglycemia and insulin resistance, leading to T2DM. The S-acylation of GLUT4 plays a key role in GLUT4 membrane translocation and glucose uptake (Ren, Sun, & Du, 2015). It has been found that inhibiting zDHHC7 can inhibit the S-acylation level of GLUT4 in adipocytes and skeletal muscle cells, and inhibit the translocation of GLUT4 in cells, thus causing hyperglycemia and decreased glucose tolerance in mice, and accelerating the progression of T2DM (Du, Murakami, Sun, Kilpatrick, & Luscher, 2017). The abovementioned studies have suggested that S-acylation occurring in pancreatic v-cells, adipocytes, and skeletal muscle cells can play a significant role in the development of T2DM by affecting normal physiological functions and glucose uptake in pancreatic β-cells, providing potential targets for the development of new therapeutic strategies (Fig. 1).

Fig. 1.

Fig. 1

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S-acylation drives molecular mechanisms of diabetes.

4. S-acylation is a common pathological mechanism of diabetic complications

4.1. S-acylation drives molecular mechanisms of diabetic cardiomyopathy

Diabetic cardiomyopathy (DCM) is a complication of structural and functional changes in the myocardium due to diabetes in the absence of coronary artery disease, which is typically characterized by altered lipid metabolism and impaired insulin signaling pathways, and usually manifests itself as lipid accumulation in cardiomyocytes, myocardial fibrosis, and cardiac systolic dysfunction, and even leads to heart failure (Huang, Luo, Liao, Li, & Feng, 2023). As the number of diabetic patients increases, the prevalence of DCM also increases to 35.0%, which not only seriously affects the quality of life of patients, but also puts a heavy burden on the public health system (Tan et al., 2020). However, the current pathogenesis of DCM is complex and involves the participation of multiple factors such as oxidative stress, inflammatory response, and cardiometabolic abnormalities, and the interaction of these mechanisms has led to imperfections in the current therapeutic schedule.

Cluster of differentiation 36 (CD36) is a membrane-localized fatty acid translocase with functions in high-affinity tissue uptake of long-chain fatty acids and contributes under excessive fat supply to lipid accumulation and metabolic dysfunction (Pepino, Kuda, Samovski, & Abumrad, 2014). Luiken et al. found that insulin stimulation in isolated myocardial rat cells resulted in a 1.5-fold increase in CD36 on the sarcolemma and a 62% decrease in intracellular CD36, suggesting that insulin could effectively promote the translocation of CD36 (Luiken et al., 2002). Furthermore, insulin stimulation has been found to promote CD36 protein synthesis, and this result suggests that CD36 expression is significantly increased in DCM (Chistiakov, Orekhov, & Bobryshev, 2017). The maturation, transport, and positioning of CD36 are regulated by S-acylation. Based on previous studies, Shu et al. supposed that the S-acylation of CD36 played an important role in DCM, which may exacerbate metabolic disorders in DCM by enhancing the stability of CD36 protein and affecting its localization on the cell membrane (Shu et al., 2022). More direct evidence was confirmed by Wang et al. that takeda G-protein-coupled receptor 5 (TGR5, a major bile acid receptor) was absent, which can increase the localization of CD36 on myocardial cell membrane by promoting ZDHHC4-mediated CD36 S-acylation, thereby exacerbating myocardial lipid accumulation and exacerbating cardiac dysfunction (Wang et al., 2024).

Sodium-calcium exchange (NCX) is a fundamental component of cardiac excitation-contraction coupling, which predominantly controls relaxation in myocytes by extruding Ca2+ from the cytosol (Xue et al., 2023). Normal functioning of the NCX ensures that excess calcium ions are discharged in a timely manner after cardiac contraction so that the heart can effectively diastole (Ottolia, Torres, Bridge, Philipson, & Goldhaber, 2013). It has been shown that fibrosis and ventricular hypertrophy have been found in chronic NCX1 ablation model as the animals age (Lotteau et al., 2021). Gök et al. found that palmitate loading of the zDHHC5 active site triggered NCX1 S-acylation, causing inactivation of NCX1, suggesting that NCX1 S-acylation is involved in the progression of DCM (Gök, Robertson, & Fuller, 2022). According to the aforementioned preclinical studies, S-acylation affects the disease progression of DCM mainly by affecting the physiological function of membrane transporters through increased fatty acid uptake and excessive Ca2+ accumulation.

4.2. S-acylation drives molecular mechanisms of DKD

DKD is a complication caused by diabetes, characterized by the gradual decrease of glomerular filtration rate and the increase of proteinuria excretion rate (Cleveland & Schnellmann, 2023). Currently, about 40% of T2DM patients worldwide suffer from DKD, however, the prevalence of DKD investigated by different countries varies greatly, and the percentage fluctuates between 27.1% and 83.7% of T2DM patients, which seriously endangers the life and health of patients (Tuttle et al., 2022, Wan et al., 2024).

In the diabetic state, the accumulation of glycosylated end products (AGEs) and the increase of oxidative stress may lead to changes in the activity of S-acylation related enzymes, which may affect the palmitoacylation level of proteins. Hou et al. found that increased expression of CD36 would lead to increased production of reactive oxygen species (ROS), which would trigger epithelial-mesenchymal transformation (EMT) and promote the progression of DKD (Hou et al., 2015). It has been found that in renal tubular epithelial cells, AGEs promote EMT and eventually lead to renal fibrosis by promoting the formation of selenoprotein N (SelN)/zDHHC6 complexes, enhancing zDHHC6 activity, and increasing CD36 S-acylation levels (Feng, 2018). In another study of DKD patients, zDHHC6 expression showed a decreased trend, and further experimental study showed that the absence of zDHHC6 in glomerular podocytes may cause damage to the glomerular podocytes by participating in cytoskeletal regulation and oxidative stress processes, which disrupts normal function of the glomeruli (Wang, 2021). Moreover, another study has observed the S-acylation of CD36 in DKD, but the mechanism of action is to promote the progress of renal fibrosis by increasing the localization of CD36 in lipid rafts, promoting the formation of copolymerization of CD36 with TLR4, and exacerbating the inflammatory infiltrate in the kidney (Xiao, 2017). The above studies have revealed that S-acylation is closely related to the progression of DKD, which destroys the normal function of kidney and aggravates kidney injury by promoting EMT, aggravating inflammatory infiltration and direct damage to podocytes.

4.3. S-acylation drives molecular mechanisms of diabetic foot ulcers

Diabetic foot ulcers (DFUs) are one of the serious and common complications of diabetes, characterized by hyperglycemia-induced vascular dysfunction, bacterial infection of wounds, peripheral vasculopathy, and imbalance of antioxidant capacity, which can lead to impaired healing diabetic microcirculatory dysfunction, amputation, and even death (Li et al., 2024, Sorber and Abularrage, 2021). It is estimated that approximately 18.6 million people worldwide suffer from DFUs each year, about 50% to 60% of ulcers will become infected, about 20% of moderate to severe infections will lead to lower extremity amputations, and the 5-year mortality rate for DFUs patients is about 30%, exceeding 70% for those with a major amputation (Armstrong, Tan, Boulton, & Bus, 2023). It can be seen that DFUs is a major global public health problem that has a serious impact on the quality of life and economic status of patients. Therefore, the pathological mechanisms of DFUs should be explored in depth with a view to better improving the prognosis of patients and reducing the social and economic burden.

The decrease of vascular maturity can hinder the normal wound healing, tissue regeneration and functional recovery, and is one of the pathogenic factors of DFUs. It has been established that decreased APT1 enzyme activity in endothelial cells from db/db mice leads to increased R-Ras S-acylation and altered R-Ras transport, resulting in decreased vascular area and reduced vascular maturation, which leads to poorer recovery from chronic hindlimb ischemia in mice, thus exacerbating the risk of lower extremity amputation (Wei et al., 2020). N-Acetylcysteine (NAC) is known to promote endothelial cell function and angiogenesis and may have therapeutic benefits in DFUs. Using a novel in vivo mouse hindlimb ischemia-amputation model, Zayed et al. demonstrated that NAC accelerated the healing of amputated limb stumps in mice by altering the vascular milieu through reduced S-acylation of Gαq, revealing the importance of S-acylation in diabetic wound healing (Zayed et al., 2017).

NLRP3 is a member of the NOD-like receptor family and is part of a cytoplasmic complex known as the NLRP3 inflammasome. When the inflammasome is activated, bioactive interleukin 1β (IL-1β) and IL-18 are produced in response to the cleavage of the Cys aspartic protease-1 (Caspase-1), and then released into the microenvironment to enhance the adaptive immune response. In diabetes, NLRP3 activation is associated with insulin resistance and microvascular and macrovascular complications of diabetes (Li et al., 2025, Nițulescu et al., 2023). Zheng et al. found that palmitate enhanced nigericin-induced Caspase-1 activation and IL-1β release in a dose-dependent manner, in addition they treated THP-1 cells with the S-acylation inhibitor, 2-BP, and found that Caspase-1 activation and IL-1β release were inhibited after treatment, these results suggest that palmitate-induced S-acylation plays a key role in the activation of NLRP3 inflammasome (Zheng et al., 2023). Lv et al. proved that there were large amounts of phenylpyruvate in DFUs, which can bind to and inhibit PPT1 activity to increase the S-acylation level of NLRP3, enhance the stability of NLRP3 protein, prevent the autophagy degradation of NLRP3, promote the activation of NLRP3 inflammasome, and thus leading to chronic inflammatory infiltration of diabetic wounds and hindering wound healing (Lv et al., 2023). The above mentioned evidences demonstrate the important role of deacylation enzymes in the refractory wounds of diabetes, where deacylation enzymes activity is inhibited in a diabetic environment and also significantly inhibit the wound healing process through two main pathways: firstly, they inhibit angiogenesis, leading to inadequate blood supply to the wound area, which affects cell growth and repair; and secondly, they aggravate the inflammatory response, which prolongs the inflammatory stage in the wound healing process, and further hindering wound healing. This finding deepens our understanding of the pathogenesis of diabetic refractory wounds and suggests that deacylation enzymes may be a new target for the treatment of such wounds in the future.

4.4. S-acylation drives molecular mechanisms of diabetic retinopathy

Diabetic retinopathy (DR) is a serious diabetic complication characterized by retinal glial network lesions and microvascular damage, and is a leading cause of blindness in adults (Perais et al., 2023). It is estimated that about 30% of patients with diabetes may develop DR, and 20 years after the diagnosis of T2DM, about 60% of patients will develop symptoms of retinopathy, which seriously affects the quality of life of patients (Bryl et al., 2022, Yang et al., 2022).

Sphingomyelin phosphodiesterase acid-like 3B (SMPDL3B) is a lipid raft enzyme associated with a variety of cellular functions, including regulation of integrin activation, cell migration, and cell survival, and may be associated with the development of various diseases (Mitrofanova et al., 2019). It has been shown that SMPDL3B deficient mice release more IL-6 and tumor necrosis factor-α (TNF-α), compared to wild-type mice, after lipopolysaccharide (LPS) stimulation, which suggests that SMPDL3B has anti-inflammatory potential (Heinz et al., 2015). Zhou et al. found that SMPDL3B silencing exacerbated DR in retinal tissues of 18-week-old db/db mice by further activating the NF-κB/NLRP3 pro-inflammatory pathway, and in their further study, they found that high glucose treatment induced the S-acylation of SMPDL3B, and blocking S-acylation by 2-BP showed a faster degradation rate in human retinal microvascular endothelial cells (HRVECs) treated with protein synthesis inhibitor cycloheximide (CHX), which was reduced by treatment with palmostatin B (a deacylation inhibitor). In response to this phenomenon, they speculated that SMPDL3B S-acylation mediated by zDHHC5 may increase the stability of SMPDL3B and inhibit the inflammatory response of retinal vascular endothelium (Zhou et al., 2024).

Contrary to the above findings, Veluthakala et al. found that diabetes induced p38 mitogen-activated protein kinase (p38 MAP) activation, which can lead to metabolic dysfunction of retinal endothelial cells and other cell types, and glucose can activate small G-protein Ras-related C3 botulinum toxin-substrate (Rac1) and nicotinamide adenine dinucleotide phosphate oxidase 2 (Nox2) in retinal endothelial cells, thus aggravating mitochondrial damage and cell apoptosis, while 2-BP can inhibit glucose induced activation of Rac1, Nox2 and p38 MAP kinases in retinal endothelial cells, reducing ROS levels. Their findings suggest that S-acylation may play a role in the signaling cascade of DR (Veluthakal, Kumar, Mohammad, Kowluru, & Kowluru, 2015). In summary, it is necessary to further explore the specific role of S-acylation in the complex pathological mechanism of DR, so as to enrich our understanding of the pathological mechanism of DR.

4.5. S-acylation drives molecular mechanisms of diabetic encephalopathy

Diabetic encephalopathy (DE) is a common complication of diabetes, which is characterized by impaired learning ability, memory loss and behavioral disorders (Nie et al., 2022). It is estimated that about 30% of people with diabetes worldwide have DE and people with DE are more likely to have Alzheimer’s disease than the general population (Zhu et al., 2022). However, the pathogenesis of DE is complex and not fully understood, so more effective and targeted treatments are needed to reduce the risk of cognitive impairment in diabetic patients.

Post-translational modification of proteins has become a key regulator of synaptic formation, transmission, and plasticity (Chato-Astrain et al., 2024, Gu et al., 2023). On the postsynaptic membrane, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR) mediate the rapid component of excitatory postsynaptic current (EPSC) and play an indispensable role in the regulation of synaptic transmission and plasticity. Many studies have shown that S-acylation is a key modification of AMPAR that regulates its synaptic expression and localization. GluA1 is one of the subunits of AMPAR. Spinelli et al. found that insulin resistance was found in the hippocampus of C57BL/6 mice after HFD, causing overexpression of zDHHC3, which led to S-acylation of GluA1, preventing its activity-dependent trafficking to the plasma membrane, impairing synaptic plasticity, and leading to cognitive decline. And interestingly, they injected 2-BP intranasally into mice and found that it counteracted the S-acylation of GluA1 in the mouse hippocampus and restored synaptic plasticity and cognitive deficits after the injection. In addition, their study shows us that HFD can lead to lipid metabolism disorder in mice, and the accumulation of palmitic acid (PA) and oleic acid (OA) in the brain provides a substrate for S-acylation, which contributes to the S-acylation of GluA1, leading to cognitive decline, suggesting that S-acylation plays a key role in the regulation of synaptic plasticity (Spinelli et al., 2017). The above evidences suggest that the excessive accumulation of PA and OA in the brain caused by lipid metabolism disorder in long-term T2DM environment provides the necessary substrate for S-acylation. These fatty acids promote the S-acylation of GluA1, leading to significant cognitive decline. This finding suggests that S-acylation plays a key role in DE by regulating synaptic plasticity.

4.6. S-acylation drives molecular mechanisms of diabetic peripheral neuropathy

Diabetic peripheral neuropathy (DPN) is the most common complication of long-term diabetes, affecting about 50% of people with diabetes. Patients with DPN usually experience symmetrical pain in the limbs, particularly in the distal end, the most typical manifestation is the gloves-and-socks sensation, which can lead to sensory dysfunction, pain, and a high risk of falls, seriously affect the quality of life of patients (Yang et al., 2022). There are currently no drugs specifically for DPN treatment on the market, the lack of efficacy and the side effects of drugs that are used to prevent and treat DPN also present serious clinical problems. Therefore, it is necessary to further explore the pathogenesis of DPN to provide reference for the effective treatment of DPN.

At present, the mechanism of ion channels in the development of DPN has been widely concerned by scholars (Zenker, Ziegler, & Chrast, 2013). Cl−HCO3− anion exchanger 3 (AE3), a member of the AE family, is expressed in the dorsal root ganglia (DRG), and is capable of mediating chloride (Cl−) inward flow in neurons, which is associated with neuronal hyperexcitability and pain hypersensitivity (Barragán-Iglesias et al., 2014, Pérez-Rodríguez et al., 2018). Cao et al. found that the S-acylation of peroxiredoxin-6 (PRDX6) in the DRG of diabetic mice can promote the co-localization of AE3 and PRDX6 on the cell membrane, promote Cl− inflow, and aggravate the pain symptoms of DPN (Cao, Wang, Zhan, & Zhang, 2022). Moreover, it has been shown that thyroid-stimulating hormone (TSH) levels are an independent risk factor for DPN and are significantly associated with DPN (Zhao et al., 2016). Fan et al. found that RSC96 cells can express functional thyroid stimulating hormone receptor (TSHR), and PA can promote the S-acylation of TSHR in cells, and aggravate the oxidative stress and apoptosis of RSC96 cells induced by TSH (Fan et al., 2021). These studies suggest that S-acylation plays an important role in the pathogenesis of DPN by promoting Cl− inflow and aggravating nerve cells injury.

4.7. Others

In addition to the complications of diabetes summarized above, there are significant associations between diabetes and diseases such as liver disease and specific types of cancer (Tomic, Shaw, & Magliano, 2022). Diabetes increases the risk of complications from NAFLD, which can also be a complication of diabetes. NAFLD is highly prevalent in patients with T2DM, with a prevalence of 56% in 49 419 patients with T2DM in a systematic review of 80 studies in 20 countries/regions, compared with an estimated global prevalence of 25% for NAFLD in the general population (Younossi et al., 2019; Younossi et al., 2016). This data highlights the close and complex association between T2DM and NAFLD. Impaired fatty acid oxidation (FAO) in mitochondria of hepatocytes causes lipid accumulation and excessive production of ROS and oxidative damage, leading to NAFLD. It has been found that S-acylation is also involved in the disease progression of NAFLD. S-acylation of FAT/CD36 is significantly upregulated in HFD-induced NAFLD model mice, which inhibits the transport of FAT/ CD36 to mitochondria, leading to the blockage of fatty acid β-oxidation, which leads to increased lipid accumulation and excessive production of ROS, and further leads to oxidative damage and aggravation of NAFLD. Inhibition of FAT/CD36 S-acylation resulted in an obvious increase in the distribution of FAT/CD36 in the mitochondria of hepatocytes, and FAT/CD36 could act as a molecular bridge between long-chain fatty acids and long-chain acyl-CoA synthetase 1 (ACSL1), increase the production of long-chain acyl-CoA, upregulate fatty acid β-oxidation and reduce hepatic lipogenesis, which alleviated the progression of NAFLD (Zeng et al., 2022).

In addition, Wang et al. further found a link between S-acylation and NAFLD in HFD mice, zDHHC5 induces S-acylation of protein kinase Cδ (PKCδ) in hypothalamic microglia, which activates microglial and neuroinflammation signaling, and causes lipid metabolism disorder and ultimately contributes to the development of steatohepatitis through hypothalamus-liver communication (Wang et al., 2024).

Furthermore, hyperglycemia has emerged as an important factor exacerbating the risk of developing hepatocellular carcinoma (HCC) (Kumar et al., 2021). It has been shown that in cirrhotic patients with diabetes, the risk of developing HCC increases by 50% (Huang, Mathurin, Cortez-Pinto, & Loomba, 2023). The phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway is an important node in regulating metabolic homeostasis. Bu et al. found that HFD or increased PA intake could promote zDHHC17/24 to catalyze AKT S-acylation and activate AKT, thus leading to the development of tumors. In their study, they also found that effective treatment of tumors can be achieved by restricting the PA diet, restricting PA synthesis, or directly targeting AKT palmitoylation (Bu et al., 2024). The abovementioned studies illustrate that S-acylation can play an important role in diabetes-induced associated liver diseases by exacerbating lipid metabolism disorder.

The key role of S-acylation in mediating the pathogenesis of diabetes and its complications is described in detail in this section (Fig. 2). These evidences provide new perspectives for understanding the common pathological mechanisms of the disease and make us realize that intervening in S-acylation may be a novel strategy for the clinical treatment of diabetes and its complications.

Fig. 2.

Fig. 2

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S-acylation drives molecular mechanisms of diabetic complications.

5. Diversity of effects on S-acylation related enzymes in diabetic environment

Due to the structural differences of various PATs and deacylation enzymes, their specific location in organelles shows heterogeneity. In addition to organelle heterogeneity, it has been found in recent years that these enzymes are also heterogeneous between cells and tissues. The study of Wild et al. revealed that PATs and deacylation enzymes in the nervous system show heterogeneity of expression specific to different brain regions and cell types, and this expression pattern plays a key role in cognitive impairment by affecting the developmental process, functional status and synaptic plasticity of neurons (Wild et al., 2022). Additionally, it has been revealed that in kidney, PATs exhibit similarly heterogeneous characteristics. Gu et al. found that zDHHC6 was predominantly expressed in podocytes, whereas zDHHC9 was significantly expressed in renal tubular epithelial cells (Gu et al., 2023).

In view of the important role of S-acylation in diabetes and its multi-organ complications, the specific effects of diabetes status on the distribution, expression and activity changes of enzymes in different tissues and cells were systematically sorted out and summarized, aiming to lay a theoretical foundation for targeted therapeutic strategies, with a view to making a breakthrough in the treatment of diabetes (Table 1). In response to the changes of PATs, zDHHC7 was found to undergo auto-acylation and increased activity in adipocytes and skeletal muscle cells (Du, Murakami, Sun, Kilpatrick, & Luscher, 2017); HFD can lead to the specific high expression of zDHHC3 in the hippocampus and hippocampal neurons of mice (Spinelli et al., 2017); zDHHC4 enhances binding to substrate protein CD36 in heart and cardiomyocytes to enhance DCM progression (Wang & Wang et al., 2024); zDHHC6 is specifically expressed in kidney, including renal tubular epithelial cells and glomerular podocytes (Wang, 2021). For deacylation enzymes, it was found that the mRNA expression level of APT1 increased but the enzyme activity decreased significantly in pancreatic β-cells (Dong et al., 2023); Meanwhile, APT1 showed low expression in endothelial cells (Wei et al., 2020); whereas, PPT1 showed low expression in macrophages (Lv et al., 2023). Based on the above, a regular rule was found, that was, the expression level or activity of PATs showed an enhanced trend in the diabetic environment, while the activity of deacylation enzymes was inhibited. These findings provide valuable clues for us to further understand the pathogenesis of diabetes and explore potential therapeutic targets. Nevertheless, current research on the mechanism of S-acylation in diabetes and its complications is still insufficient, especially with regard to the changes in enzyme expression and activity in disease states.

Table 1.

Effects on diversity of S-acylation related enzymes in environment of diabetes and its complications.

Enzymes Tissue localization Changes References
zDHHC7 Fat and muscle Increasing activity of zDHHC7 Du, Murakami, Sun, Kilpatrick, & Luscher, 2017
zDHHC4 Heart/cardiomyocytes Increasing binding of zDHHC4 to substrate protein CD36 Wang et al., 2024
zDHHC5 Heart Increasing auto-acylation of zDHHC5 Gök, Robertson, & Fuller, 2022
Retinal tissue/HRVECs Increasing binding of zDHHC5 to substrate protein SMPDL3B Zhou et al., 2024
DRG Only candidate enzymes catalyzing S-acylation of protein were preliminarily screened Cao, Wang, Zhan, & Zhang, 2022
Hypothalamus zDHHC5 can exacerbate disease by binding to PKCδ Wang et al., 2024
zDHHC9 Kidney Decreasing expression of zDHHC9 Gu et al., 2023
zDHHC6 Kidney/renal tubular epithelial cell Increasing activity of zDHHC6 Feng, 2018
Kidney/glomerular podocytes Decreasing expression of zDHHC6 Wang, 2021
zDHHC3 Hippocampus Increasing expression of zDHHC3 Spinelli et al., 2017
zDHHC17/24 Liver Increasing expression of zDHHC17/24 Bu et al., 2024
APT1 Pancreatic β-cell Upregulating APT1 mRNA but decreasing APT1 enzyme activity Dong et al., 2023
Endothelial cell Decreasing activity of APT1 Wei et al., 2020
PPT1 Macrophage Decreasing activity of PPT1 Lv et al., 2023
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6. Feasible strategies and challenges of targeted protein S-acylation in treatment of diabetes and its complications

Through the in-depth exploration of the above, it is found that protein S-acylation plays a central role in diabetes and its complications. Given this, an innovative therapy targeting the S-acylation process, which changes the biological properties of proteins by precisely regulating their S-acylation levels, is gradually showing great potential in the treatment of a variety of diseases, providing a new perspective for the treatment of diabetes and its complications (Table 2).

Table 2.

Therapeutic agents targeting S-acylation related enzymes and mechanism of action.

Means of treatment Drug names Mechanisms References
Broad spectrum inhibitors 2-BP Irreversible pan-deacylation agent, but it can inhibit APT1 and APT2 Rana et al., 2018
Cyanomethyl-N-myracrylamide (CMA) A new broad-spectrum DHHC inhibitor can inhibit zDHHC2, 4, 5, 6, 9, 11, 13, 14, 15, 16, 18, 20, 23 and 24 Azizi et al., 2021
Tunicamycin Inhibition of PATs activity by competition with palmitoyl-CoA Hu, Tao, & Wu, 2021
3-(1-Oxo-hexadecyl)oxiranecarboxamide Inhibition of PATs activity by competition with palmitoyl-CoA Varner et al., 2003
Compound 8i (A covalent S-acylation inhibitor with 2-BP and CMA as lead compounds) In preliminary studies, compound 8i may be a broad-spectrum zDHHC inhibitor Yu et al., 2024
Compound V
2-(2-Hydroxy-5-nitro-benzylidene)-benzo[b]thiophen-3-one		 Blocking auto-acylation of zDHHC Jennings et al., 2009
Palmostatin B Broad-spectrum inhibitor of APT1/2, PPT1, ABHD17A/B/C as well as other lipid-processing serine hydrolases Won, Cheung & Martin, 2018
Palmostatin M Rusch et al., 2011
Hexadecylfluorophosphonate (HDFP) Broad-spectrum inhibitor of APT1/2, PPT1, ABHD 10, ABHD17A/B/C Fan et al., 2024
Specific inhibitors MY-D-4 (2-BP derivative) Inhibition of zDHHC3,7 Hong et al., 2021
Local anesthetics (prilocaine, lidocaine, procaine, and ropivacaine) Weakening zDHHC15 transcripts Fan et al., 2021
Bis-piperazine back bone-based compounds Inhibition of zDHHC9 Hamel et al., 2016
TTZ-1, TTZ-2 Inhibition of zDHHC2, 3, 7, 15, 17 Salaun et al., 2022
ML211 Inhibition of APT1, APT2, PPT1 and ABHD11 Won, Cheung & Martin, 2018
ABPP probes Inhibition of APT1, APT2 Rusch et al., 2011
JJH254 Cognetta et al., 2015
Bis-boronic acid derivative Zimmermann et al., 2013
ML348 Inhibition of APT1 Yuan et al., 2024
ML349 Inhibition of APT2 Won et al., 2016
GNS561 Inhibition of PPT1 Harding et al., 2022
HCQ Fan et al., 2024
Lys05 Rebecca et al., 2019
DQ661 Nicastri, Rebecca, Amaravadi, & Winkler, 2018
DC661 Rebecca et al., 2019
HDFP-alk Martin, Wang, Adibekian, Tully, & Cravatt, 2011
ABL303 (ML257) Inhibition of ABHD10 Zuhl et al., 2011
MIDA-boronates Adachi et al., 2015
Rocaglate-derived β-lactone Lajkiewicz, Cognetta III, Niphakis, Cravatt, & Porco Jr, 2014
1,3,4-Oxadiazol-2(3H)-one derivatives Inhibition of ABHD16A Ahonen et al., 2018
12-Thiazole abietanes Ahonen et al., 2018
KC01, KC02 Kamat et al., 2015
ABD957 Inhibition of ABHD17 Remsberg et al., 2021
Chinese herbal medicines Artemisinin Covalently binding and inhibiting zDHHC6 Qiu et al., 2022
Artemether Blocking binding of substrate protein PKCδ to zDHHC5 Wang et al., 2024
Benzosceptrin C Targeted binding and inhibition of zDHHC3 Wang et al., 2024
Curcumin Inhibition the auto-acylation of zDHHC3 Coleman, Soung, Surh, Cardelli, & Chung, 2015
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6.1. Broad-spectrum inhibitor

The most widely used broad spectrum PATs inhibitor is 2-BP, which irreversibly inhibits S-acylation by covalently modifying the active site of DHHC enzyme with Cys (Rana et al., 2018). In diabetic mice, the use of 2-BP can alleviate disease symptoms by inhibiting S-acylation in the hippocampus and liver (Bu et al., 2024, Spinelli et al., 2017). In addition, Lan et al. have developed a novel broad-spectrum DHHC inhibitor, CMA, which has been shown to work in vivo and in vitro (Azizi et al., 2021). There are also broad-spectrum inhibitors designed on the basis of 2-BP and CMA as lead compounds, such as 3-(1-oxo-hexadecyl)oxiranecarboxamide (Varner et al., 2003), compound 8i (Yu et al., 2024), compound V that blocks auto-acylation of zDHHC (Jennings et al., 2009), and tunicamycin that blocks S-acylation of zDHHC by irreversibly inhibiting the PATs to block the S-acylation process (Hu, Tao, & Wu, 2021). Most of the current studies have chosen 2-BP as a PATs inhibitor; However, it has been shown that 2-BP also inhibits APT1 and APT2 (Abrami et al., 2021). Although the newly developed CMA was not be found to disturb with the activity of APT1 and APT2, the inhibitory effect of CMA on part of zDHHC was only confirmed in the study due to various technical difficulties, and the binding of CMA and zDHHC had not been comprehensively analyzed (Lan, Delalande, & Dickinson, 2021). Therefore, the development of more broad-spectrum inhibitors targeting DHHC to ensure the rigor and accuracy of experimental studies is still an urgent problem to be solved.

The current broad spectrum inhibitors for deacylation enzymes are divided into palmostatin B, palmostatin M and HDFP. Palmostatin B, a classical broad-spectrum inhibitor, has been shown to block the activities of APT1/2, PPT1, ABHD17A/B/C (Won, Cheung & Martin, 2018); Palmostatin M is similar to palmostatin B, but it has higher activity in cells, which may have some advantages in application (Rusch et al., 2011); HDFP can inhibit the activity of APT1/2, PPT1, ABHD10 and ABHD17A/B/C (Fan et al., 2024). In the study of Zhou et al., Palmostatin B was used to inhibit deacylation and regulate the protein stability of substrate SMPDL3B, thus affecting the pathophysiological process of DR (Zhou et al., 2024). It is preliminarily suggested that these inhibitors may be potential drugs for the clinical treatment of T2DM.

6.2. Specific inhibitor

Although there are currently available inhibitors specific to zDHHC, they are still lacking. At present, most of the specific DHHC inhibitors are used in tumors, for example, a variety of local anesthetics can inhibit zDHHC15 to play a potential role in treating glioblastoma stem cells (Fan et al., 2021). Moreover, MY-D-4 (2-BP derivative) was found to inhibit zDHHC3/7 (Hong et al., 2021); bis-piperazine back bone-based compounds inhibited zDHHC9 (Hamel et al., 2016); TTZ-1 and TTZ-2 inhibited zDHHC2, 3, 7, 15, 17 (Salaun et al., 2022). A total of 23 species of zDHHC have been identified in mammals, but there are only specific inhibitors for a few of these zDHHCs, and further development is needed for specific inhibitors for other zDHHCs.

There are several specific inhibitors for deacylation enzymes, such as ML348 and ML349 are competitive inhibitors of APT1 and APT2, respectively (Won et al., 2016, Yuan et al., 2024); ML378, ABPP probe, JJH254, and bis-boronic acid derivative inhibit APT1/2 (Cognetta et al., 2015, Rusch et al., 2011, Won et al., 2018, Zimmermann et al., 2013); ML211 inhibits PPT1, ABHD11 in addition to APT1/2 (Won, Cheung & Martin, 2018); GNS561, HCQ, Lys05, DQ661, DC661, HDFP-alk inhibit PPT1 (Fan et al., 2024, Harding et al., 2022, Martin et al., 2011, Nicastri et al., 2018, Rebecca et al., 2019); ABL303 (ML257), MIDA-boronates, rocaglate-derived β-lactone inhibit ABHD10 (Adachi et al., 2015; Lajkiewicz, Cognetta III, Niphakis, Cravatt, & Porco Jr, 2014; Zuhl et al., 2011); 1,3,4-oxadiazol-2(3H)-one derivatives, 12-thiazole abietanes, KC01, KC02 inhibit ABHD16A (Ahonen et al., 2018, Kamat et al., 2015); ABD957 can be used as a selective covalent inhibitor of ABHD17 (Yuan et al., 2024). However, from what has been described in the previous section, it is found that a decrease in APT1 enzyme activity leads to abnormal insulin secretion, which in turn causes damage to pancreatic β-cells, thus exacerbating the symptoms of diabetes (Dong et al., 2023). Thus, in the specific pathological setting of diabetes, inhibition of deacylation enzymes activity, rather than bringing about the desired therapeutic effect, accelerates disease progression. In response to this pathology, the development of deacylation agonists to restore or enhance enzyme activity has emerged as a promising therapeutic strategy aimed at providing new therapeutic avenues for mitigating disease progression by reversing the trend of reduced enzyme activity.

6.3. Chinese herbal medicines

Notably, Chinese herbal medicines have a long history of use in the treatment of diabetes and are believed to regulate blood glucose, improve pancreatic islet function, and mitigate the complications of diabetes (Tan et al., 2022, Tian et al., 2019). In addition to focusing on the development of small molecule inhibitors, the exploration of Chinese herbal medicines as a potential therapeutic strategy also shows broad prospects. For example, Qiu et al. found in anticancer research that artemisinin, as an antimalarial drug molecule, can covalently bind and inhibit zDHHC6, thereby reducing the S-acylation of carcinogenic protein NRas to exert anticancer activity (Qiu et al., 2022). Wang et al. also provided evidence to support this treatment strategy, in their study, it was found that the antimalarial drug artemether can effectively block the binding of substrate protein PKCδ to zDHHC5 by directly targeting PKCδ in microglia cells, and then inhibit the S-acylation of PKCδ, which had an inhibitory effect on the progression of fatty liver (Wang et al., 2024). Additionally, other studies have found that benzosceptrin C and curcumin can inhibit zDHHC3 to exert anticancer activity (Coleman et al., 2015, Wang et al., 2024). Notably, Curcumin has been found to improve diabetes by improving pancreatic β-cells function, preventing β-cells failure, reducing insulin resistance, and alleviating multi-organ complications caused by diabetes (Chuengsamarn et al., 2012, Parsamanesh et al., 2018). Given that lipid accumulation due to abnormal lipid metabolism can provide a substrate for palmitoylation, this phenomenon suggests that a variety of traditional Chinese medicines that regulate lipid metabolism, such as Picrorhizae Rhizoma, Astragali Radix, Salviae Miltiorrhizae Radix et Rhizoma, Crataegi Fructus, and Alismatis Rhizoma, may help treat diabetes and its complications by targeting inhibition of target proteins to bind to the palmitoylase enzyme or inhibiting the enzyme activity (Ai et al., 2022, Dai et al., 2021).This phenomenon opens up an innovative avenue for drug discovery and development by exploring the potential of targeting PATs in nature to treat diseases, and promises to provide us with a range of effective tools for treating related diseases.

6.4. Covalent inhibitors targeting substrate cysteine residues

S-acylation, a biological process, involves the S-acylation of a substrate protein by PATs through specific interactions with Cys residues of the substrate protein. Lv et al. used the online software CSS-Palm to predict the potential S-acylation sites of NLRP3, and in the course of their experiments they found that the mutation of Cys residue 6 (C6) in NLRP3 mainly hindered its S-acylation and effectively alleviated the inflammatory infiltration in DFUs (Lv et al., 2023). Although there are practical difficulties in directly mutating S-acylated Cys in the substrate protein in patient therapy, we may be able to explore covalent inhibitors that target Cys residues. By blocking the binding of substrate protein to the PATs reversibly or irreversibly, the S-acylation process can be effectively inhibited. However, most of the covalent inhibitors that can target Cys residues are currently used in serious diseases such as cancer and autoimmune diseases, such as ibrutinib, acalabrutinib, afatinib and dozens of other covalent drugs targeting Cys have been successively approved by the FDA for the treatment of cancer. However, these drugs can develop resistance after a period of clinical treatment of cancer, and many Cys are also involved in the formation of disulfide bonds in extracellular proteins, and it is difficult to covalently modify them (Zhong et al., 2021). Despite the theoretical potential of this strategy, there are still many challenges to overcome in its practical application. These phenomena make it necessary to further consider whether the use of covalent drugs targeting Cys is irreplaceable in the treatment of diabetes and its complications.

6.5. Others

In addition, we can also use the introduction of S-acylation at the protein site to treat the disease and show its beneficial side. Zhou et al. found that the S-acylation of SMPDL3B mediated by zDHHC5 can inhibit inflammation and alleviate the progression of DR, but the site at which SMPDL3B undergoes S-acylation was not thoroughly investigated (Zhou et al., 2024). Numerous epidemiological and experimental studies have demonstrated that patients who suffer from obesity or T2DM have a higher risk of cognitive dysfunction. On this basis, it has been suggested that food intake regulatory peptides may be promising candidates for the treatment of obesity, T2DM, and cognitive deficits (Maletínská, Popelová, Železná, Bencze, & Kuneš, 2019). Among them, anorexigenic prolactin-releasing peptide (PrRP), as a key molecule released in the central nervous system, acts cooperatively with leptin to regulate energy metabolism (Ellacott, Lawrence, Rothwell, & Luckman, 2002). Mráziková et al. developed a novel PrRP analog S-acylated at position 11 (palm11-PrRP31), and this innovative modification not only enhanced its bioavailability, but also demonstrated the effect of lowering body weight (BW) and food intake in diet-induced obesity (DIO) mice in applications. In particular, the modified PrRP analog also demonstrated neuroprotective effects in the FA/FA rat model (Čermáková et al., 2019, Holubová et al., 2018, Mráziková et al., 2022). The above research results not only revealed the important role of S-acylation in regulating the function of bioactive peptides, but also pointed out a new direction for future diabetes treatment, that is, by accurately introducing S-acylation at specific protein sites, to develop a more efficient and safe novel treatment strategy.

7. Conclusions and prospects

S-acylation, a lipid modification, can play a key role in a variety of diseases, and at the beginning of this paper we speculated that S-acylation may be the common pathological mechanisms in diabetes and its multi-organ complications. Therefore, this review systematically summarized and concluded the mechanism of S-acylation mediating diabetes and its complications, providing a new perspective for understanding the pathological mechanism of these complex diseases, and providing evidence support for the targeted S-acylation treatment of diabetes. In this review, it was found that S-acylation can be the pathological mechanism of diabetes and its complications. Specifically, abnormally elevated levels of S-acylation significantly accelerated the progression of the disease, further highlighting its critical role in the development of diabetes. Furthermore, it was also found that the disease state can have a wide range of effects on PATs and deacylation enzymes. Firstly, the distribution of enzymes in the diabetic environment showed tissue and cell heterogeneity, and some enzymes showed obvious enrichment in specific tissues, and participated in the progression of the disease through S-acylation. Secondly, in the process of combing and summarizing, it was found that the diabetic environment not only affected the distribution of enzymes, but also had a significant impact on the activity or expression level of enzymes. In the diabetic state, the expression level or activity of PATs showed a consistent upward trend, while the activity of deacylation enzymes was inhibited. Notably, it has been suggested that APT1 mRNA levels in pancreatic β-cells tend to increase in the diabetic environment, which may be a compensatory response by the body to cope with the impaired function of depalmitoylation (Dong et al., 2023). Therefore, the relationship between changes in APT1 mRNA levels and enzyme activity can be further focused in future studies aimed at deepening our understanding of the complex mechanism of S-acylation dysfunction in diabetic states. Based on the critical role of S-acylation in diabetes and its complications, we propose that targeting S-acylation be the focus of therapeutic strategies to address this complex and pervasive health problem.

However, current research on the role of S-acylation in mediating the pathogenesis of diabetes and its complications is still insufficient, especially the lack of insight into the expression profile of DHHC in disease states. Therefore, it is necessary for future studies to further focus on the dynamic changes of transcriptional activity, protein expression level, enzyme activity and histocellular specific localization of PATs under the pathological conditions of diabetes. This initiative will point the way forward for subsequent studies to further explore the specific mechanisms of these enzymes in enriched organs and their regulatory relationships with each other, providing new strategies and ideas for achieving precise treatment and prevention of diseases.

Based on the deep understanding that S-acylation is the common pathological mechanism of diabetes and its complications, we propose that it can achieve the purpose of targeting protein S-acylation for the treatment of diabetes and its complications by blocking the key link in the S-acylation process. From what has been described above, we can conclude that there are four possible treatment strategies. First, developing a class of inhibitors that can not only avoid interfering with the activity of deacylation enzymes, but also broadly inhibit DHHC family members or target specific DHHC. At the same time, more experiments are needed to verify the inhibitory effect of CMA on other DHHC members in order to screen out more effective broad spectrum inhibitors of DHHC. Secondly, for the special pathological environment of diabetes, the development of agonists that can target deacylation enzymes can be used to reverse or alleviate the progression of diabetes by promoting deacylation. Third, we can learn from the research ideas of Wang et al., and actively search for Chinese herbal medicines that can effectively block the S-acylation process like artemether, which may provide valuable resources for the development of new anti-diabetes drugs, and be expected to bring new breakthroughs in the treatment of diabetes. Fourth, to evaluate and explore the necessity and feasibility of developing covalent inhibitors targeting substrate Csy in diabetes, a metabolic disease, with a view to opening up a new therapeutic approach by occupying the S-acylated site in the substrate protein and preventing DHHC from binding to it, so as to achieve therapeutic effects.

In addition to the above-mentioned therapeutic strategies, we can also promote the progress of targeted S-acylation in the treatment of diseases in other ways. To explore potential drug synergies, inhibitors can be used in conjunction with Chinese herbal medicines to inhibit S-acylation through multiple pathways to achieve better efficacy. With the continuous progress of technology, artificial intelligence and machine learning methods can be used to accelerate the development of new drugs, by predicting potential drug targets and simulating drug and target interactions, rapid screening of potential drug compounds. Moreover, Dong et al. found that APT1-deficient mice raised under normal dietary conditions had enhanced insulin secretion capacity and improved glucose tolerance. Only when these mice received HFD did their glucose tolerance become impaired and the area of pancreatic β-cells decreased, eventually leading to β-cells failure (Dong et al., 2023). Bu et al. also found that HFD or direct additional PA intake can increase S-acylation and aggravate HCC (Bu et al., 2024). From this we conclude that lipid metabolism disorder and lipid accumulation can provide reactive substrates for S-acylation, suggesting that there may be therapeutic potential for lipid-lowering statins or the anti-obesity drug orlistat, which play a therapeutic role by lowering fatty acids in vivo to block substrate availability to S-acylation. Taken together, S-acylation may be a common mechanism of diabetes and its complications, and the development of targeted S-acylation drugs may be an effective strategy for clinical prevention and treatment of diabetes and its complications in the future.

CRediT authorship contribution statement

Ruiting Liu: Data curation, Visualization, Writing – original draft. Nuo Xu: Data curation, Visualization, Writing – original draft. Xuejiao Song: Visualization, Data curation. Yanying Li: Data curation. Jie Bu: Visualization. Runtao Su: Writing – original draft. Hong Guo: Project administration. Chen Jiang: Project administration. Pengwei Zhuang: Conceptualization, Supervision, Writing – review & editing. Yanjun Zhang: Conceptualization, Supervision, Writing – review & editing. Qingsheng Yin:. Conceptualization, Supervision, Writing – review & editing.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

This work is supported by National Natural Science Foundation of China (No. 82304909), National Natural Science Foundation of China (No. 82174112), Tianjin Science and Technology Innovation Base Construction (No. 24ZYJDSY00280).

Contributor Information

Yanjun Zhang, Email: zyjsunye@163.com.

Qingsheng Yin, Email: carrysable@163.com.

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