HIF-1α, a key transcription factor, regulates cellular responses to hypoxia. Upon stabilization, HIF-1α translocates into the nucleus, binding to hypoxia-responsive elements to initiate transcription of genes (38), including those related to inflammation such as interleukin-1β (IL-1β) (9, 39). Prolyl hydroxylases (PHDs), part of the α-KG-dependent dioxygenase family, are integral to cellular oxygen sensing and regulate HIF-1α stability. An increase in cytoplasmic succinate, following PHD inhibition, activates HIF-1α, thereby amplifying the transcription of pro-inflammatory genes (40). Although this activation is beneficial for cellular adaptation to hypoxic conditions, excessive succinate can induce a “pseudohypoxia” state (41, 42), enhancing HIF-1α activity even in oxygen-rich environments, a condition frequently observed in tumors with mutated SDH (43). Consequently, inhibiting PHDs hinders HIF-1α degradation even in oxygen-rich environments, hence triggering the activation of a spectrum of target genes (41).

Additionally, succinate has been shown to indirectly stabilize HIF-1α by inducing the production of ROS (44, 45). ROS mediates the oxidation of Fe²⁺ to Fe³⁺, inhibiting PHD activity that relies on Fe²⁺. This inhibition leads to the activation of HIF-1α (46). In macrophages activated by lipopolysaccharide (LPS), elevated succinate levels enhance UQ reduction, leading to “reverse electron transport (RET)” which channels electrons back to respiratory complex I (47, 48). This process significantly increases ROS production, further stabilizing HIF-1α through PHD inhibition (40) ( Figure 2 ). As a result, high levels of succinate not only disrupt ATP synthesis and oxidative phosphorylation but also enhance ROS generation, amplifying pro-inflammatory signals (49, 50).

Moreover, increased cytoplasmic succinate levels promote post-translational modifications, such as succinylation, which regulates the activity of metabolic enzymes in mitochondria (51–53). In LPS-activated macrophages, a metabolic shift occurs from reliance on mitochondrial ATP production to dependence on aerobic glycolysis, with pyruvate kinase M2 (PKM2) playing a critical role (54). Hypersuccinylation of PKM2 facilitates its nuclear translocation, promoting the formation of a PKM2-HIF-1α complex at the IL-1β gene promoter, as illustrated in Figure 2 . This interaction intensifies the severity of dextran sulfate sodium (DSS)-induced colitis in mice (54, 55). Additionally, the sirtuin family enzyme SIRT5 is implicated in modulating PKM2 succinylation and its enzymatic activity, thus potentially attenuating pro-inflammatory responses in macrophages (54).

Upon release from cells, succinate interacts with its membrane receptor, SUCNR1, which is sensitively responsive to extracellular succinate levels (56). SUCNR1 is expressed across a variety of tissues, including the kidney, small intestine, liver, spleen, retina, and heart, as well as within specific immune cells such as macrophages, dendritic cells (DCs), and some T-cell subsets. This wide distribution underscores its significant role in modulating immune responses (17, 28, 57). The expression of SUCNR1 is influenced by the extracellular concentration of succinate, which under normal physiological conditions in plasma and urine remains below the activation threshold of the receptor (58). However, these concentrations are approximately twofold lower than the EC₅₀ for SUCNR1, indicating that a substantial increase in succinate levels is necessary to fully engage the receptor (59). The signaling pathways activated by SUCNR1 involve two G proteins—Gq and Gi (11, 60). Activation of protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) cascades, along with calcium mobilization, are mediated through the Gq pathway, whereas the inhibition of cyclic adenosine monophosphate (cAMP) is facilitated by the Gi pathway (12). These mechanisms highlight the critical role of the succinate-SUCNR1 axis in the regulation of inflammatory processes.

While intracellular succinate is acknowledged as a necessary pro-inflammatory signal, its extracellular presence not only amplifies pro-inflammatory responses but, under certain conditions, can also exert anti-inflammatory effects (27). In induced neural stem cells (iNSCs) and somatic neural stem cells (NSCs) that utilized to mimic the inflammatory cascade, Peruzzotti-Jametti et al. showed that succinate induces an anti-inflammatory response through SUCNR1 signaling, leading to the release of prostaglandin E2 (PGE2), which modulates various cell types within the inflammatory microenvironment. Additionally, the absence of SUCNR1 in NSCs significantly reduces anti-inflammatory actions both in vitro and in vivo ( 61). Succinate has been proposed as a potential therapeutic for severe sepsis, primarily by enhancing ATP generation, which is crucial for rescuing tissues from the bioenergetic dysfunction associated with sepsis (62). Recent research suggests that activating SUCNR1 in macrophages within adipose tissue could initiate an anti-inflammatory response (63). Moreover, succinate may inhibit the release of inflammatory mediators like IL-6, IL-1β, nitric oxide (NO), and tumor necrosis factor (TNF) in inflammatory macrophages, independently of SUCNR1 signaling (64). However, succinate can also exacerbate inflammatory conditions by enhancing oxidative stress or driving inflammation, as observed in macrophages exposed to LPS, in mouse models of antigen-induced arthritis, and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis (9, 16, 65). The role of succinate in inflammation and its broader physiological and pathological implications are increasingly focused on the dynamics of its receptor, SUCNR1 (66, 67). The dual pro- and anti-inflammatory capacities of succinate during inflammation appear to be highly context-dependent.

Rheumatoid arthritis, a chronic inflammatory disorder, is closely associated with metabolic dysregulation, which influences its progression and symptom severity (95, 96). Succinate levels are notably high in the synovial fluid of both antigen-induced arthritis mice and patients with rheumatoid arthritis (16, 97). Metabolic profiling has identified succinate as a distinctive metabolite differentiating rheumatoid arthritis from other arthropathies (98). This accumulation triggers macrophages in the synovial fluid to release IL-1β, mediated through SUCNR1 signaling (16). Additionally, succinate in synovial fibroblasts activates the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome, enhancing IL-1β secretion (99). Treatment of endothelial cells with LPS and exposure of these cells along with synovial fibroblasts to hypoxic conditions result in succinate accumulation, which induces angiogenesis through the release of vascular endothelial growth factor (VEGF), associated with HIF-1α stabilization and SUCNR1 activation by extracellular succinate (91). This endothelial activation and increased angiogenesis contribute to the pathogenesis of rheumatoid arthritis by facilitating leukocyte recruitment and migration and promoting hyperplasia in the synovial pannus (100). Moreover, SUCNR1 functions as a chemotactic gradient sensor, orchestrating DC migration toward lymph nodes, thereby leading to the proliferation of Th17 cells. These cells are closely associated with articular lesions and are known to intensify inflammation, neutrophil infiltration, mechanical hyperalgesia, and bone erosion within joints (80). These findings underscore the critical role of succinate in regulating inflammation in rheumatoid arthritis (101).

IBD, encompassing two primary phenotypes, Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic disorder characterized by recurrent inflammation of the gastrointestinal tract (102). Studies have shown increased levels of succinate in the sera, plasma, and intestinal tissues of IBD patients, along with enhanced expression of SUCNR1 in these tissues (65, 103, 104). This is supported by findings in mice, where those colonized with fecal samples from CD and UC patients displayed higher fecal succinate levels compared to those colonized from healthy individuals, indicating that succinate accumulation is a metabolic hallmark of IBD-associated dysbiosis (105). SUCNR1 not only triggers fibroblast activation and stimulates pro-inflammatory responses in macrophages but also contributes to colitis and intestinal fibrosis in murine models (65). Furthermore, a relationship has been reported between increased succinate levels in the gut lumen and microbiome dysbiosis in both IBD patients and animal models of intestinal inflammation (30, 106).

Recent studies indicate that circulating succinate levels are significantly elevated in both rodent models and patients with obesity (93, 107). The inflammation of adipose tissue, a hallmark of obesity, drives insulin resistance and subsequently, diabetes mellitus. Succinate and its receptor SUCNR1 exacerbate this obesity-induced inflammation, promoting the infiltration of macrophages into adipose tissue, which is a key contributor to the glucose intolerance observed in type 2 diabetes (21). Interestingly, the effects of SUCNR1 deficiency in macrophages vary depending on their location and the level of inflammation. In subcutaneous fat, SUCNR1-deficient macrophages tend to exhibit a pro-inflammatory phenotype, unlike their wild-type counterparts. Conversely, in visceral fat, which is typically pro-inflammatory, macrophages show reduced inflammation when SUCNR1 is deficient (63). Previous studies have demonstrated that the succinate-SUCNR1 axis plays a crucial role in promoting type 2 immunity in the gut, acting as an essential anti-inflammatory regulator (108). While obesity is associated with increased succinate levels (93), it often features impaired SUCNR1 signaling, leading to what is described as a “succinate-resistant state” (63). In SUCNR1-deficient mouse models, succinate-SUCNR1 signaling initiates type 2 immune responses in the intestine, facilitates the development of barrier-promoting goblet cells, mitigates high-fat diet (HFD)-induced mucosal barrier impairments and intestinal dysbiosis, and ultimately exhibits anti-obesity effects. This research highlights the protective function of the succinate-SUCNR1 axis against intestinal barrier dysfunction induced by HFD (109).

Atherosclerosis is a multifactorial pathological condition characterized by vascular inflammation and the accumulation of lipids and fibrous elements in the vessel walls (110). Elevated levels of succinate may act as a mediator driving the progression of atherosclerotic lesions by activating the SUCNR1 pathway, which results in phenotypical transformations of smooth muscle cells, macrophage polarization, and endothelial cell dysfunction (111). Studies have shown that patients with coronary heart disease exhibit notably higher levels of succinate and IL-1β compared with healthy individuals, with a positive correlation between succinate and IL-1β levels. The glycolytic metabolism triggered by the release of succinate is evident in atherosclerotic pathology. This, in turn, stimulates the succinate/IL-1β signaling pathway through SUCNR1, thereby exacerbating inflammatory responses (112).

In the metabolism of pro-inflammatory macrophages, Mills et al. confirmed the critical role of mitochondrial SDH in regulating LPS-induced gene expression. Specifically, elevated succinate oxidation via active SDH increases the expression of inflammatory genes, while inhibition of SDH fosters an anti-inflammatory phenotype (113). Malonate, a competitive inhibitor at the carboxylate site of SDH, and its cell-permeable prodrug dimethyl malonate (DMM), which produces malonate intracellularly, lead to succinate accumulation. DMM has been shown to effectively suppress the expression of pro-inflammatory genes, such as IL-1β and HIF-1α, and simultaneously enhance the expression of anti-inflammatory genes like IL-1RA and type I IFN-inducible genes (113). Interestingly, DMM does not affect TNF-α levels, suggesting a specific pathway of action (113). In conditions like cellular hypoxia in synovial fibroblasts and ischemia, SDH is proposed to function in reverse, converting fumarate to succinate (8). DMM exhibits anti-inflammatory effects by inhibiting the HIF-1α/VEGF axis in hypoxia-treated synovial fibroblasts, preventing succinate accumulation, and inhibiting angiogenesis (91). Moreover, DMM reduces succinate accumulation during ischemia and controls oxidation during reperfusion, thereby decreasing mitochondrial ROS generation and attenuating ischemia-reperfusion injury (8). The malonate ester prodrug diacetoxymethyl malonate shows greater potency than DMM, owing to its accelerated esterase hydrolysis (114). Although succinate accumulates via different mechanisms in LPS-treated macrophages and other conditions, inhibition of SDH similarly reduces IL-1β production (91).

Itaconate, an endogenous small molecule synthesized by the enzyme cis-aconitate decarboxylase, acts as an immunomodulator and inhibits SDH, impacting metabolic and inflammatory processes in cells (115). Due to its structural similarity to succinate, itaconate was identified decades ago as a competitive inhibitor of SDH. This inhibition leads to elevated succinate accumulation and reduced mitochondrial ROS production, affecting mitochondrial respiratory chain complex I (116). Itaconate demonstrates anti-inflammatory properties in vitro and in vivo by modulating SDH levels, mitochondrial respiration, and cytokine production (IL-1β, IL-18, IL-6, IL-12, NO, and HIF-1α, but not TNF-α), particularly during macrophage activation and ischemia-reperfusion injury (117). Further studies show that SDH inhibition by itaconate also mitigates cerebral ischemia-reperfusion injury (118, 119). As an SDH inhibitor, itaconate manages oxidative stress and enhances physiological outcomes associated with ischemia-reperfusion injury (120). Research has revealed that both endogenous (117) and exogenous (121) itaconate-mediated SDH inhibition affects mitochondrial function. Importantly, while targeting succinate through this pathway offers valuable insights into its physiological roles, the therapeutic application must be approached cautiously, given the pivotal role of SDH in cellular energetics ( Figure 5 ).

In recent years, there has been increasing attention on the role of SUCNR1 in various pathophysiological processes, significantly highlighting its potential as a therapeutic target (122). The accumulation of succinate in various inflammatory states further underscores the importance of targeting SUCNR1 to mitigate the detrimental effects of excess succinate (28). Advances in understanding the structure-function relationship of SUCNR1 have facilitated the development of structure-based antagonists (123). Systematic structure-activity relationship studies have identified compounds “2c” and “4c” as effective SUCNR1 antagonists both in vitro and in vivo. Moreover, compounds “5g” and “7e”, which are structurally distinct and orally bioavailable, have shown potential as promising leads in drug development (13). NF-56-EJ40, a high-affinity SUCNR1 antagonist, effectively reduces succinate/IL-1β signaling in macrophages and HUVECs, demonstrating a potent inhibitory effect (112, 124). Additionally, NF-56-EJ40 substantially attenuates succinate-mediated gene expression in primary human anti-inflammatory macrophages (77). A topically applied gel formulation of the SUCNR1 antagonist compound “7a” has been shown to reduce inflammatory events and osteoclastogenesis in vivo ( 125). The therapeutic efficacy of “7a” is directly attributed to the suppression of SUCNR1-mediated succinate signaling (126).

Furthermore, the transplantation of cells expressing SUCNR1 into an inflammatory environment is also a promising strategy to mitigate excess succinate. Mesenchymal stem cell (MSC) transplantation, known for its ability to differentiate into various cell types, is utilized to facilitate the repair and regeneration of damaged tissues (127). This method has been demonstrated to effectively decrease succinate levels in tissues, subsequently triggering beneficial effects in adjacent areas. Specifically, upon transplantation, adipose-derived MSCs absorb succinate, decreasing its accumulation and shifting macrophage to pro-inflammatory macrophages, which mitigates DSS-induced colitis in mice (76). Similarly, when transplanting NSCs into the cerebrospinal fluid of mice with experimental autoimmune encephalomyelitis, succinate secreted by type 1 mononuclear phagocytes binds to SUCNR1 on NSCs, thereby reducing the production of succinate in the cerebrospinal fluid and preventing the progression of neuroinflammation (61).

However, the critical involvement of SUCNR1 in essential physiological processes and its significance in regulating energy homeostasis must be carefully considered. The systemic application of SUCNR1 antagonists could lead to severe adverse effects due to the disruption of these essential functions. Additionally, while antagonists serve to inhibit receptor function, there might be scenarios where activating SUCNR1 could offer therapeutic benefits. The challenge lies in employing SUCNR1 antagonists effectively in the treatment of SUCNR1-mediated diseases without compromising its normal or advantageous functions (73).