Succinyl-CoA serves as the primary donor for succinylation, and its concentration reversibly regulates the process of succinylation (Chinopoulos, 2021). Overall decrease in the mitochondrial succinyl-CoA pool, decreased myofibril protein succinylation, which may promote heart failure (Ali et al., 2020). Succinyl-CoA deficiency, impeding ketone oxidation in skeletal muscle, is often associated with acute episodes of ketoacidosis (Mechchate et al., 2023). Enzymes affecting succinyl-CoA production indirectly regulate succinylation levels. For instance, α-ketoglutaric dehydrogenase (α-KGDH) promotes succinylation by increased succinyl-CoA produced in propionate and/or ketone body metabolism in nerve cell, accelerating progression of neurodegenerative diseases (Dobolyi et al., 2020).

Additionally, succinate or other metabolites can also impact the extent of succinylation (Guillon et al., 2022). Accumulation of ischemic succinate increased the succinylation of the Rho family GTPase Cdc42, resulting in neural stem cell proliferation inhibition and aggravated cerebral ischemia/reperfusion (I/R) injury (Huang et al., 2023). Therefore, targeting on succinylation is considered as a potential therapeutic approach for I/R (Liu et al., 2020).

In recent years, significant progresses have been made in the study of succinylases, with the identification of several new succinylases, such as lysine acyltransferase 2A (KAT2A), and carnitine palmitoyltransferase 1A (CPT1A) (Lu et al., 2021).

KAT2A is also known as General Control Non-derepressible 5 (GCN5), whose histone succinylases activity plays a crucial role in tumorigenesis (Tong et al., 2020). KAT2A-mediated H3-K79succ regulates gene expression and β-catenin stability in tumor cells, contributing to tumor cell proliferation and invasion (Tong et al., 2021). In prostate cancer (PCa) cells, KAT2A-mediated CTBP- K46 and K280succ can repress transcription suppressing activity of it, thus acting as an oncogene (Zhou et al., 2023).

CPT1A has also been identified as a potential succinylases. In gastric cancer (GC), CPT1A-mediated LDHA-K222succ reduces its binding to SQSTM1 and inhibits the degradation of LDHA, as well as promotes GC invasion and proliferation.

Sirtuin5(SIRT5) possess NAD⁺-dependent desuccinylation activity (Green and Storey, 2021; Zhang and Goetzman, 2021), reducing succinylation levels of mitochondrial proteins (Chinopoulos, 2021), and subsequently modulating the target activities of numerous substrate proteins to maintain metabolic homeostasis (Lukey et al., 2020). SIRT5 protein reduces LDHA-K118succ in PCa, by which it may be used as a new strategy to prevent the progression of castration-resistant PCa for treatment (Kwon et al., 2023). SIRT5 can inhibit peroxisom-induced oxidative stress, liver protection and inhibit the development of hepatocellular carcinoma by reducing the succinylation level of peroxisomal ACOX1 (Chen et al., 2018). Consequently, SIRT5 is considered a pivotal regulator in various cancers and inhibitors targeted succinylation may serve as promising anti-tumor (Shen et al., 2023).

Additionally, it has been discovered that SIRT7 possesses desuccinylase activity, primarily in nucleus (Bai et al., 2022). It serves important functions such as stimulating the expression of ribosomal RNA, facilitating DNA damage repair, and balancing chromatin compaction (Lagunas-Rangel, 2023). These findings emphasize the critical role of SIRT7 in protecting chromatin structure, controlling innate immune regulation and ensuring reproductive protection during stem cell senescence (Raza et al., 2024).

As mentioned above, protein succinylation, as a conservative PTM, participates in diverse biological processes in bacteria, fungi, viruses and human cells (Yuan T. et al., 2020).

Succinylation plays an important role in protein biosynthesis and carbon metabolism of bacteria/fungi and antibiotic biosynthesis. The succinylation levels of vancomycin-intermediate Staphylococcus aureus (VISA) decreased with enhanced vancomycin tolerance (Yang et al., 2024). EchA19-K132, 139succ in Mycobacterium tuberculosis (Mtb) is a negative feedback regulator of cholesterol metabolism in the host (Bonds et al., 2020). In addition, increased succinylation exerting favorable inhibition of Aspergillus fumigatus infection in terms of fungicidal and enhanced macrophage killing effect (Chen et al., 2023). These findings provide valuable insights into the mechanism of desuccinylase inhibitors in the treatment of ITR-resistant fungal infections.

Succinylation dysregulation may play a critical role in viral infection. SARS-CoV-2, the pathogen responsible for the COVID-19 pandemic, induces succinylation of several crucial enzymes in the tricarboxylic acid cycle (TCA), leading to inhibition of cellular metabolic pathways (Liu et al., 2022). Notably, IFN-α clears hepatitis B virus (HBV) cccDNA through depressed GCN5-mediated H3-K79succ (Yuan Y. et al., 2020). Therefore, inhibitors targeting succinylation exhibit significant antiviral effects, providing provide a new avenue for anti-viral treatment.

Dysregulation of succinylation affects the infiltration of immune cells and the expression of immune genes, thereby promoting the malignant development of cancer (Lu et al., 2021). Succinylation induces the expression of pro-inflammatory genes in T cells and activates HIFα in M1 macrophages, leading to the inflammation-cancer cycle (Shen et al., 2023).

Succinylation is tissue heterogeneous during tumorigenesis (Lu and Han, 2022), and it is involved in the regulation of various tumorigenesis and progression through different substrate targets or signaling pathways (Zhang X. et al., 2023).

In general, succinylation can have a pro-cancer effect. It is significantly high-expressed in various tumor tissues such as lung cancer, PCa, HCC, PDAC and glioma (Zhang X. et al., 2023; Zhou et al., 2023). Elevated succinylation is closely related to tumor invasion/metastasis ability and patient survival prognosis (Lukey et al., 2020). There are two mechanisms for the pro-cancer effect of succinylation. One involves inhibiting degradation of succinylated substrate, thus promoting proliferation, invasion and migration of tumor cells. Upregulation of CPT1A and downregulation of SIRT5 synergistically promotes S100A10-K47succ and fibrillin 1 (FBN1) K672succ, resulting in the accumulation of S100A10 and FBN1 in GC cells and further promoting tumor progression (Wang et al., 2022). Another mechanism is that succinylation helps maintain the redox balance of cancer cells and promotes their proliferation. In colon cancer, elevated PKM2-K498succ promotes the production of more ATP during glucose starvation and maintains tumor cell survival during nutrient depletion (Qi et al., 2019).

It is paradoxical that high citrate synthase (CS) K393 and 395succ significantly inhibits the proliferation and migration of colon cancer cells (Ren et al., 2020), and the detection of increased SIRT5 expression levels in lung cancer and breast cancer (Lu and Han, 2022). This suggests that increased succinylation contributes to the suppression of certain tumors.

The concentration of succinyl-CoA in the heart tissue is significantly higher than that in any other organs. Succinylation is closely associated with cardiomyocyte metabolism and its dysregulation is widely involved in cardiovascular disease (CVD) (Weis et al., 2022). Highly succinated proteins highly enriched in thoracic aortic aneurysms (TAA) and thoracic aortic dissection (TAD) Promise to be potential diagnostic markers and therapeutic targets for aortic diseases (Zhang H. et al., 2023). Accumulation of succinylated ECHA leads to decreased ATP production in the myocardium, reduced cardiac ejection fraction, and ultimately to hypertrophic cardiomyopathy (Hershberger et al., 2018). During myocardial ischemia, SIRT5 significantly promotes the desuccinylation of IDH2, a key enzyme involved in TCA, maintaining mitochondrial homeostasis and improving myocardial fibrosis, reduce the incidence of heart failure (Chang et al., 2021).

The analysis of succinylated proteomics data and transcriptomics data revealed that the mRNAs matched by most differentially succinylated proteins were especially highly expressed in neurons and astrocytes (Deng et al., 2021). Abnormal succinylation may be linked to abnormal cortical nerve anatomy and could potentially contribute to the pathological processes of various neurological disorders (Ning et al., 2022). In Alzheimer’s disease, increased succinylation level of amyloid precursor protein disrupts its normal proteolytic processing, leading to the accumulation of Aβ and plaque formation. Additionally, succinylation of tau protein promotes its aggregation into tangles and impairs microtubule assembly (Yang Y. et al., 2022). An elevated succinylation level of pyruvate dehydrogenase complex (PDHC) in the hippocampus may downregulate mitochondrial energy metabolism, while potentially contributing to parasympathetic activity dysregulation, anxiety and depression (Artiukhov et al., 2022). Therefore, studying the mechanism and function of desuccinylation can provide a foundation for targeted therapy of nervous system diseases.

Dysregulation of succinylation is associated with reproductive disorders (Yang et al., 2018). Reduction of LDHC-K317succ reduces production of ATP, leading to asthenospermia (Yang et al., 2020). Inhibition succinylation of germ cell can result in reproductive injury. Analysis of postmenopausal women aged from 55 to 70 years old indicate that succinylation of apolipoprotein A-I and A-II, hemoglobin subunit α and haptoglobin are elevated in patients with osteoporosis and osteopenia (Zhang et al., 2019). This suggests that elevated succinylation is associated with aging and age-related diseases. (Du et al., 2018).