T1D is an autoimmune disorder characterized by progressive immune-mediated destruction of pancreatic β cells, culminating in absolute insulin deficiency (29,30). In the absence of endogenous insulin, glucose homeostasis is markedly disrupted, resulting in chronic hyperglycaemia and lifelong reliance on exogenous insulin therapy. The metabolic consequences of T1D extend beyond impaired glucose regulation, affecting lipid and amino acid metabolism, and increasing vulnerability to systemic complications, including both macrovascular and microvascular damage (31–33). Although β-cell-directed autoimmunity defines T1D, the broader metabolic alterations across peripheral tissues remain insufficiently characterized.

Direct evidence associating lysine succinylation with T1D is currently limited; however, findings from experimental models have implicated the dysfunction of SCOT as a potential mechanistic association (34). SCOT, a central enzyme in ketone body utilization and a key consumer of succinyl-CoA, exhibits reduced activity in T1D models due to inhibitory tyrosine nitration and decreased 3-oxoacid CoA-transferase 1 expression. This impairment is particularly detrimental within the metabolic context of T1D. In contrast to T2D, absolute insulin deficiency in T1D drives unrestrained lipolysis and excessive hepatic ketogenesis. The resulting surge in ketone body production necessitates efficient SCOT-mediated turnover; however, suppression of SCOT activity compromises this process. Such metabolic disequilibrium may limit succinyl-CoA utilization, leading to its accumulation within the mitochondrial matrix, potentially promoting pathological hypersuccinylation in susceptible tissues, including the myocardium (35,36).

Emerging data suggested that mitochondrial succinyl-CoA accumulation is not simply a metabolic by-product, but may foster broader cellular dysfunction (37,38). Beyond SCOT-dependent mechanisms, the characteristics of the T1D inflammatory environment may directly affect succinylation dynamics, specifically the balance between spontaneous modification and SIRT5-mediated desuccinylation. β-cell destruction is orchestrated by pro-inflammatory cytokines, including IL-1β and IFN-γ, which promote pronounced oxidative stress and mitochondrial injury in pancreatic islets (39,40). Although direct validation in T1D remains limited, evidence from related metabolic disorders, such as non-alcoholic fatty liver disease (NAFLD) and metabolic cardiomyopathy, has indicated that oxidative stress can attenuate SIRT5 activity, diminishing de-succinylation capacity (41,42). It may therefore be hypothesised that cytokine-driven redox imbalance in T1D suppresses SIRT5 function, resulting in the accumulation of hypersuccinylated mitochondrial proteins that further compromise β-cell bioenergetics and viability.

In addition, protein succinylation may contribute to the immunopathogenesis of T1D. PTMs can generate neoepitopes that initiate or amplify autoimmune responses (43,44). As aforementioned, succinylation induces notable structural and physicochemical alterations in target proteins. These modifications may theoretically generate neoantigens or modify antigen processing and presentation by major histocompatibility complex molecules in β cells. In comparison, analogous mechanisms have been established for other PTMs, such as citrullination in autoimmune diseases (45); whether aberrant succinylation functions as a source of neoantigens in T1D remains an important and unresolved question requiring further investigation.

T2D arises from the interplay between peripheral insulin resistance and an insufficient compensatory increase in insulin secretion (46,47). In the early stages, pancreatic β cells increase insulin secretion to compensate for reduced insulin sensitivity. This adaptive response depends on precise regulation of glycolytic flux, TCA cycle activity and lipid metabolism in response to glucose, incretin signalling and pharmacological stimuli, such as metformin and sodium-glucose cotransporter-2 inhibitors (48). However, persistent exposure to hyperglycaemia and elevated lipid levels imposes chronic metabolic stress that progressively exhausts β-cell reserve. The ensuing dysfunction is characterized by a depletion of TCA cycle intermediates, including citrate, malate and oxaloacetate, increased oxidative stress and impaired insulin secretory capacity (49). Obesity notably increases the risk of T2D by exacerbating insulin resistance and sustaining low-grade inflammation, which further affects metabolic homeostasis (50). Although classical disruptions in TCA cycle dynamics and fatty acid oxidation (FAO), including metabolic inflexibility and incomplete lipid oxidation, are well documented (51,52), the contribution of emerging PTMs, particularly protein succinylation, to β-cell stress adaptation remains incompletely understood and merits further investigation.

Experimental data have indicated that aberrant succinylation, specifically pathological hyper-succinylation, directly impairs β-cell function in T2D, a central event in disease progression. In Goto-Kakizaki rats, a widely used T2D model, both expression and activity of SCOT are diminished (53). Reduced SCOT function leads to intracellular accumulation of succinyl-CoA, which adversely affects β-cell function by impairing glucose-stimulated insulin secretion (54). Targeted silencing of SCOT in insulinoma cells has been shown to markedly attenuate glucose-stimulated insulin secretion, underscoring its key metabolic role. In addition, chronic glucolipotoxicity, a defining feature of T2D, induces β-cell apoptosis (55,56). Furthermore, experimental overexpression of SIRT5 counteracts this process by upregulating mitochondrial anti-apoptotic proteins Bcl-2 and Bcl-XL, preventing cytochrome c release and inhibiting downstream caspase-3/7 activation, preserving β-cell viability and function (57). These findings support the premise that excessive succinylation is detrimental to β cells under diabetic stress conditions.

Beyond β-cell failure, dysregulated succinylation also impairs insulin signalling in peripheral tissues. In hepatic tissue from diet-induced obesity and diabetes models, abnormal succinylation has been identified on numerous proteins integral to insulin signalling pathways, including insulin receptor substrate 1. Proteomics analyses have mapped nine atypical succinylation sites across 268 metabolically relevant hepatic proteins (58). Such modifications may disrupt downstream signalling from the insulin receptor, reducing cellular insulin responsiveness and aggravating systemic insulin resistance. Pharmacological inhibition of SCOT using diphenylbutylpiperidines (DPBPs) has been shown to improve glycaemic control in experimental animal obesity models, specifically diet-induced obese mice. However, their clinical utility is limited by marked off-target effects. Namely, as potent dopamine D2 receptor antagonists, DPBPs have been associated with extrapyramidal symptoms, sedation and cardiac adverse events, including QT interval prolongation (59,60). Despite these limitations, these observations underscore the therapeutic potential of targeting the succinyl-CoA metabolic axis in T2D (60).

At the molecular level, protein succinylation is primarily determined by the balance between intracellular succinyl-CoA availability and desuccinylase activity. In T2D-associated metabolic stress, increased succinyl-CoA production can overwhelm the regulatory capacity of SIRT5, leading to widespread hypersuccinylation and subsequent metabolic impairment (61). Enhancement of SIRT5 activity has been shown to ameliorate select metabolic abnormalities, such as β-cell apoptosis, hepatic insulin resistance and cardiac lipotoxicity.

Subsequent to the acute enzymatic disturbances in metabolic pathways, the present review will further discuss more persistent epigenetic alterations that sustain cellular dysfunction. The concept of ‘metabolic memory’ refers to the continued progression of vascular complications even after glycaemic control has been restored. Although this effect has classically been attributed to oxidative stress and the accumulation of advanced glycation end-products, emerging evidence has identified aberrant lysine succinylation as a stable molecular imprint capable of perpetuating dysfunction beyond the initial hyperglycaemic exposure (62–64).

In contrast to transient phosphorylation, succinylation produces a marked charge reversal and steric constraint, changes that can stabilize metabolic enzymes in maladaptive conformations (65). During hyperglycaemia, excessive succinyl-CoA production exceeds the desuccinylation capacity of SIRT5. Restoration of SIRT5 activity is often hindered not only by substrate overload but also by NAD⁺ depletion and oxidative stress-induced transcriptional repression (66). This imbalance promotes sustained hypersuccinylation of mitochondrial proteins, such as the PDC and carnitine palmitoyltransferase 2 (CPT2), and contributes to cytosolic succinate accumulation (16). Elevated succinate functions as an oncometabolite that inhibits prolyl hydroxylases, leading to stabilization of hypoxia-inducible factor-1α and maintenance of a ‘pseudo-hypoxic’ state that persists beyond the original metabolic insult (67,68).

Beyond its effects on metabolic enzymes, succinylation associates altered metabolic flux with long-term transcriptional reprogramming. Rather than requiring direct transport of succinyl-CoA into the nucleus, recruitment of the α-KGDH complex enables localized nuclear generation of succinyl-CoA (8). This compartmentalized metabolite pool supplies substrate for histone succinylation. By altering chromatin structure, these epigenetic modifications promote an open configuration at pro-inflammatory gene loci (69). Therefore, prior metabolic stress becomes embedded within the epigenome, sustaining pathogenic transcriptional programs despite subsequent therapeutic normalization of glycemia.

Obesity is a complex metabolic disorder defined by excessive adipose tissue accumulation resulting from chronic positive energy balance (70). It constitutes a major global health challenge and is a primary risk factor for T2D, cardiovascular disease and NAFLD (71). Obesity induces marked metabolic reprogramming in tissues, including adipose depots in the liver, promoting hepatic steatosis and triggering endoplasmic reticulum stress in adipocytes (72). These disturbances contribute to systemic insulin resistance and broader metabolic dysfunction (73–75). Within this altered metabolic environment, widespread shifts in PTMs occur, with protein succinylation emerging as a key regulatory mechanism.

Brown adipose tissue (BAT), the principal site of non-shivering thermogenesis, is particularly dependent on tightly regulated succinylation dynamics (76,77). Thermogenic capacity in BAT is mediated by UCP1, the stability and activity of which are influenced by succinylation status. SIRT5-mediated desuccinylation of UCP1 (notably, at residues K56 and K151) supports protein stability and thermogenic efficiency. Under obesogenic conditions, reduced SIRT5 activity increases UCP1 succinylation, impairing BAT thermogenesis. The consequent decline in energy expenditure promotes weight gain, highlighting the therapeutic relevance of targeting the SIRT5/UCP1 regulatory axis to restore metabolic flexibility in BAT.

In addition, a parallel succinyl-CoA-dependent pathway operates in adipose tissue macrophages (ATMs), whereby metabolic signalling directly promotes inflammatory activation. In this setting, the glutaminolysis/AMP-activated protein kinase (AMPK)/succinyl-CoA synthetase ADP-forming subunit β (SUCLA2) axis drives pro-inflammatory responses. ATP generated through glutaminolysis suppresses AMPK activity, limiting phosphorylation-dependent inhibition of SUCLA2. Enhanced SUCLA2 activity further increases intracellular levels of succinyl-CoA and succinate, stimulating excessive IL-1β production. This cascade promotes inflammatory polarization of ATMs, suppresses thermogenic function, reduces energy expenditure and exacerbates obesity (78).

The metabolic consequences of increased succinyl-CoA production are context dependent. When supplied as alternative metabolic fuels, substrates that elevate succinyl-CoA may exert beneficial effects. Dodecanedioic acid (DC12), a medium-chain dicarboxylic acid, undergoes β-oxidation in tissues expressing the acyl-CoA oxidase 1 isoform, generating succinyl-CoA that enters the TCA cycle. Administration of DC12 has been shown to increase whole-body energy expenditure, decrease adiposity, reduce hepatic lipid accumulation and improve glucose tolerance, mitigating obesity by enhancing mitochondrial substrate cycling (79).

The liver further illustrates the context-specific nature of succinyl-CoA metabolism. Hepatic steatosis, a common obesity-associated complication (80), has been shown to be notably attenuated in ob/ob mice when hepatic SIRT5 activity is augmented via genetic overexpression (18). These findings underscore how the metabolic impact of SIRT5 is highly dependent on tissue type and pathological context, rather than uniformly protective or deleterious (Fig. 3).

Context-dependent metabolic consequences of succinylation extend beyond adipose tissue to the cardiovascular system. DbCM is a distinct myocardial disorder characterized by structural and functional abnormalities in individuals with diabetes, occurring independently of hypertension, coronary artery disease or notable valvular pathology (81). Its development is largely driven by metabolic disturbances, including impaired metabolic flexibility, mitochondrial dysfunction and lipotoxicity, that culminate in myocardial fibrosis, hypertrophy, and progressive impairment of both diastolic and systolic function. Key pathogenic mechanisms include altered substrate utilization, mitochondrial dysfunction, oxidative stress and diminished ATP generation (82,83).

Ketone bodies represent an efficient energy substrate for the heart, particularly under conditions of metabolic stress. In the diabetic myocardium, tyrosine nitration-mediated inhibition of SCOT reduces its enzymatic activity by 24–39% (35). Impaired SCOT function limits the conversion of ketone bodies into acetyl-CoA, aggravating the energetic deficit characteristic of DbCM. As aforementioned, although pharmacological inhibition of SCOT may transiently enhance glucose tolerance, its potential cardiotoxic effects highlight the need to maintain balanced ketone metabolism in the diabetic heart (84).

The PDC, a key association between glycolysis and the TCA cycle, represents an additional metabolic control point disrupted in DbCM (85). Sustained exposure of cardiomyocytes to hyperglycaemia and elevated fatty acids increases intracellular succinyl-CoA concentrations, promoting succinylation of the pyruvate dehydrogenase E1 subunit α-1. This modification suppresses PDC activity, restricting pyruvate flux into the TCA cycle and further compromising metabolic flexibility, the capacity of the heart to alternate between glucose and lipid substrates. Over time, this metabolic inflexibility contributes to myocardial hypertrophy and diastolic dysfunction, establishing a self-perpetuating cycle of metabolic stress, excessive succinylation, PDC inhibition and progressive energetic decline (17).

Regulatory control by SIRT5 is similarly disrupted in DbCM. Mitochondrial impairment and oxidative stress can attenuate SIRT5 activity, reducing desuccinylation efficiency and exacerbating mitochondrial metabolic failure (12). SIRT5 also directly regulates CPT2, a key enzyme in mitochondrial fatty acid β-oxidation (86). Deficiency of SIRT5 markedly increases succinylation of CPT2 at lysine 424, suppressing its enzymatic function and impairing FAO. Accumulation of long-chain acylcarnitines subsequently promotes lipotoxic damage and worsens cardiac dysfunction. By comparison, experimental SIRT5 overexpression has been shown to preserve CPT2 activity through desuccinylation, enhancing FAO efficiency and mitigating lipotoxic stress in the diabetic myocardium (61).

Similar to the myocardium, the kidneys are highly susceptible to metabolic injury driven by aberrant succinylation, particularly through epigenetic and microvascular pathways. DKD, also termed diabetic nephropathy, is among the most prevalent microvascular complications of diabetes and remains the leading cause of chronic kidney disease and end-stage renal failure worldwide, affecting ~50% of patients with T2D globally (87). It is characterized by progressive damage to both glomerular filtration structures and renal tubular compartments (88). Persistent hyperglycaemia, frequently compounded by hypertension, initiates structural and functional deterioration that culminates in albuminuria, a clinical hallmark of DKD (89). As injury advances, the glomerular filtration rate progressively declines, impairing the capacity of the kidneys to eliminate metabolic waste, often leading to irreversible renal failure (90).

Epigenetic dysregulation has emerged as a central mechanism underlying the aberrant transcriptional programs observed in DKD (91,92). Expression of the histone succinyltransferase KAT2A is notably increased in affected kidneys. KAT2A mediates succinylation at the spermidine/spermine N1-acetyltransferase family member 2 (SAT2) promoter, enhancing its transcriptional activation. Upregulated SAT2 expression exacerbates renal injury by promoting iron-dependent ferroptosis and amplifying inflammatory signalling, including increased production of IL-1β, IL-6 and TNF-α (93,94). These processes accelerate glomerular and tubular injury, positioning the KAT2A/H3K79 succinylation/SAT2 axis as a pivotal epigenetic driver of DKD progression (95).

Succinylation dynamics similarly modulate mitochondrial integrity in renal cells. Astragaloside IV, a bioactive natural compound, confers renoprotective effects in part through activation of CPT1A. Enhanced CPT1A activity restores appropriate succinylation of 17β-hydroxysteroid dehydrogenase 10 (HSD17B10) at lysine 99 (96). Properly succinylated HSD17B10 maintains the structural stability and enzymatic function of mitochondrial ribonuclease P, a key regulator of mitochondrial RNA processing (97), attenuating oxidative stress and reducing tubular epithelial injury.

Podocyte dysfunction represents another hallmark of DKD and desuccinylation appears protective in this setting. The flavonoid quercetin-4′-O-β-D-glucopyranoside upregulates SIRT5 expression in podocytes (98). SIRT5-mediated desuccinylation of NIMA related kinase 7 (NEK7), a kinase key in activating the NLR family pyrin domain containing 3 (NLRP3) inflammasome, disrupts the NEK7/NLRP3 interaction (99). This interference suppresses podocyte pyroptosis, reduces oxidative stress and helps preserve podocyte structure and function (100).

However, SIRT5 activation does not uniformly confer benefit. In mesangial cells under hyperglycaemic conditions, SIRT5 expression is elevated, promoting the desuccinylation of the tumour suppressor p53. Although total p53 protein levels remain unchanged, desuccinylation attenuates its transcriptional activity (101,102). Diminished p53 function reduces expression of downstream targets such as p21 and 14-3-3σ, facilitating mesangial cell proliferation and excessive extracellular matrix deposition, including collagen and laminin (103). These alterations directly contribute to glomerulosclerosis and the progression of DKD.

Although SIRT5 activity may aggravate pathological remodelling in renal mesangial cells, its function in the retina appears consistently protective. DR develops as chronic hyperglycaemia progressively injures the retinal microvasculature within the light-sensitive neural tissue at the posterior segment of the eye. Structural weakening of retinal capillaries increases vascular permeability, permitting leakage of plasma constituents or blood into the retinal parenchyma. The resulting oedema and microvascular damage contribute to progressive visual impairment (104,105).

Aberrant protein succinylation has emerged as an early contributor to neurodegenerative processes in DR. Under hyperglycaemic conditions, increased succinylation of optineurin (OPTN) at lysine 108 has been observed in experimental retinal models. This modification is associated with disrupted autophagic flux in retinal ganglion cells, compromising cellular homeostasis. SIRT5-mediated desuccinylation of OPTN reverses this effect, restores autophagic function and confers neuroprotection. These findings delineate the SIRT5/OPTN axis as a central regulatory mechanism and a promising therapeutic target in early-stage DR (106). A comprehensive overview of organ-specific regulatory mechanisms and their pathological consequences is provided in Table I.