Succinylation is the chemical process where a succinyl group (–CO–CH₂–CH₂–COO^-) covalently binds to the ε-amino group of a lysine residue via enzymatic or non-enzymatic pathways, forming an amide bond (Papan et al., 2014). The core biochemical characteristics of this modification are charge inversion and induced steric hindrance. Under physiological conditions, the lysine ε-amino group carries a positive charge (+1), whereas the introduced succinyl group is negatively charged (−1). This charge inversion from +1 to −1 significantly alters the electrostatic landscape of the protein surface, consequently influencing its conformation, enzymatic activity, protein–protein interactions, and subcellular localization (Zhang et al., 2011; Ramazi and Zahiri, 2021). In contrast, acetylation introduces a neutral acetyl group (–CO–CH₃), which neutralizes the positive charge (from +1 to 0) (Charidemou and Kirmizis, 2024). Furthermore, the succinyl group is structurally longer and bulkier than the acetyl group, generating more pronounced steric hindrance that can disrupt local protein architecture and functional interfaces (Hirschey and Zhao, 2015). Consequently, succinylation exerts a more substantial impact on protein structure and function compared to acetylation, enabling it to act as an efficient metabolic “switch” that rapidly responds to changes in cellular metabolic states.

The precise regulation of protein function relies on a complex network of multiple PTMs. As a modification that is highly sensitive to the cellular metabolic state, succinylation engages in extensive crosstalk with other major PTMs such as acetylation, ubiquitination, methylation, and phosphorylation. These intricate interactions expand the dimensions of protein functional regulation and provide new insights into integrated regulatory mechanisms that link cellular metabolism, epigenetics, and the immune microenvironment (Figure 2).

NAFLD, recently redefined as MASLD, is pathologically characterized by the severe dysregulation of hepatic lipid metabolism (Rong et al., 2022; Zhang and Brandman, 2025). Succinylation plays a central role in metabolic dysregulation during NAFLD/MASLD by regulating the activity of key metabolic enzymes in hepatocytes (Cheng et al., 2016) (Figure 3).

Hepatitis B virus (HBV) infection is a leading cause of viral hepatitis in China and a major driver of liver fibrosis, cirrhosis, and HCC. HBV covalently closed circular DNA (cccDNA) forms minichromosomes within infected hepatocyte nuclei, serving as a template for viral RNA transcription, and constituting a critical factor in persistent infection and treatment resistance (Ren et al., 2025). The transcriptional activity of cccDNA is regulated by histone modifications, of which succinylation has emerged as a critical epigenetic mechanism and a potential therapeutic target (Figure 3).

Liver fibrosis is a reparative response to chronic liver injury, characterized by excessive extracellular matrix deposition. Cirrhosis constitutes the terminal stage of fibrosis, manifesting as structural destruction and a functional decrease of the liver (Ginès et al., 2021; Somnay et al., 2024). The pathogenesis of liver fibrosis and cirrhosis is complex and involves interactions between multiple cell types, signaling pathways, and molecular events (Horn and Tacke, 2024; Gilgenkrantz et al., 2021). Analyzing the progression of this disease from the perspective of succinylation aids in elucidating the underlying pathophysiological mechanisms and provides a crucial theoretical foundation for the development of novel targeted therapeutic strategies (Figure 3).

HCC development is accompanied by significant metabolic reprogramming that influences the tumor microenvironment (Lin et al., 2024; Yang et al., 2025d). Succinylation exerts multidimensional regulatory effects on HCC by mediating metabolic reprogramming and reshaping the tumor immune microenvironment, thereby promoting malignant proliferation, invasion, metastasis, and immune evasion (Figure 3).

Liver failure is a clinically critical syndrome characterized by the rapid deterioration of liver function, multi-organ dysfunction, and extremely high mortality. Its pathophysiological mechanisms involve multiple pathways, including systemic inflammatory response, immune metabolic dysregulation, and oxidative stress, ultimately leading to mitochondrial dysfunction and disruption of hepatic microenvironment homeostasis (Luo et al., 2023). Succinylation, a functional metabolic regulatory hub, plays a central role in mitochondrial dysfunction and inflammatory immune regulation during liver failure (Figure 3).

Multiple commonly used clinical drugs exert their therapeutic effects by modulating succinylation, thereby offering new perspectives for the treatment of liver diseases. Beyond its classic immunomodulatory effects, the frontline antiviral drug IFN-α downregulates KAT2A expression via the JAK-STAT pathway, thereby reducing H3K79 succinylation on cccDNA and inhibiting HBV transcription (Yuan et al., 2020). This finding provides a novel mechanistic perspective for IFN-α′s antiviral action and validates KAT2A as a potential therapeutic target. Metformin hydrochloride activates the AMPK-SIRT5 axis, promoting SIRT5-mediated desuccinylation of ECHA. This improves glucose and lipid metabolism and restores mitochondrial function, revealing a new molecular basis for its use in NAFLD/MASLD (Tang et al., 2025). Glibenclamide inhibits the succinyltransferase activity of CPT1A, thereby blocking its mediation of mitochondrial fission factor (MFF) succinylation, which subsequently affects the formation of mitochondria-associated membranes and the activation of the lipogenic transcription factor SREBP1 (Zhu Y. et al., 2025). In HCC, glibenclamide activates the JNK pathway, increases intracellular ROS levels, induces apoptosis, and suppresses tumor progression (Yan et al., 2017). Additionally, it ameliorates drug-induced liver injury by inhibiting hepatic bile acid secretion (Le Vee et al., 2022). These findings collectively demonstrate the potential of glibenclamide in the treatment of liver diseases through the modulation of the succinylation pathway. Aspirin competitively binds to the p65 subunit of NF-κB, inhibiting its nuclear translocation. This blocks the transcriptional activation of the HAT1 promoter, downregulates HAT1 expression, and reduces K99 succinylation levels of PGAM1. Ultimately, it exerts antitumor effects by inhibiting the Warburg effect (Wang et al., 2023). Lidocaine promotes SIRT5-mediated desuccinylation of histone H2B-like proteins, demonstrating its therapeutic potential for the targeted treatment of HCC (Chen X. et al., 2024). Furthermore, acetylhydroxylysine, a clinically used urinary tract infection treatment and potent OXCT1 inhibitor, demonstrates significant synergistic antitumor effects when combined with lenvatinib in a mouse liver tumor model (Guo et al., 2025). These studies reveal novel mechanisms by which existing drugs regulate succinylation modification, providing theoretical support for repurposing old drugs. The findings also validate the feasibility of targeting key succinylation enzymes and lay the foundation for developing combination therapies based on complementary mechanisms of action.

Significant progress has been made in the development of small molecules that target key enzymes involved in succinylation. Multiple compounds have demonstrated clear therapeutic potential. The SIRT7 inhibitors 2800Z and 40569Z specifically bind to the active site of the enzyme, effectively inhibiting its desuccinylation activity. Preclinical studies demonstrate synergistic antitumor effects when combined with sorafenib (Zhang et al., 2021; Zhang C. et al., 2023). The HDAC2-specific inhibitor CAY10683 mitigates intestinal injury in acute liver failure by blocking the mitochondrial apoptotic pathway and reducing the expression of the pro-apoptotic protein Bax expression (Liu et al., 2019). Compound D574-0246 effectively inhibited the dual enzyme activity of OXCT1, reduced LACTB succinylation in a dose-dependent manner, and suppressed tumor growth (Liu H. et al., 2025). Naturally derived inhibitors exhibit several unique advantages. Aurora fibroblastin A specifically binds to the Gln299 and Asp305 residues of SIRT7, inhibiting its enzymatic activity. This promotes succinylation and subsequent proteasomal degradation of PRMT5, thereby activating the cGAS-STING pathway and inducing HSC senescence (Wang J. et al., 2025). Hydroxytyrosol exerts hepatoprotective effects by inhibiting HDAC1/2 activity, activating hepatic autophagy, and alleviating oxidative stress and inflammation (Fan et al., 2024). Furthermore, compounds such as astragaloside IV (Zhu and Lu, 2024), crocin (Chen H. et al., 2025), and paeoniflorin (Chen R. et al., 2024) play crucial roles in treating tumors and inflammatory diseases by downregulating KAT2A expression and inhibiting succinylation of its substrate protein.

Studies on small-molecule agonists have primarily focused on SIRT5 activation. 2,3,5,4′-Tetrahydroxystyrene-2-O-β-d-glucoside (TSG) enhances the stability of SIRT5 mRNA by strengthening the interaction with the RNA-binding protein SRSF2, thereby increasing its protein expression levels. This upregulation promotes CPT1A activity and ameliorates hepatic lipid metabolism disorders (Zhang S. et al., 2022). Puerarin activates the AMPK pathway to upregulate SIRT5 expression, specifically catalyzing desuccinylation of the key site K385 on ALDH2. This enhances ALDH2 enzyme activity, promotes the clearance of aldehyde substances, and effectively alleviates oxidative stress damage (Yu et al., 2024). Natural products, such as quercetin (Chang et al., 2024; Chang et al., 2021), resveratrol (Yang et al., 2025e; Zhang L. et al., 2025), and ligustrazine (Shi et al., 2025), directly activate SIRT5 to promote the desuccinylation of substrates, such as isocitrate dehydrogenase 2 (IDH2) and dual-specificity phosphatase 1 (DUSP1), thereby maintaining mitochondrial energy homeostasis. In addition to natural products, the synthetic small-molecule agonist, MC3138, selectively activates SIRT5 to regulate glutamine metabolism. Its combination with gemcitabine or the phosphate chelator lanthanum acetate has synergistic antitumor effects, offering new directions for developing SIRT5-targeted combination therapies (Hu et al., 2021; Barreca et al., 2023).

These studies validate the feasibility of succinylation-regulating enzymes as therapeutic targets and lay a solid foundation for the development of novel targeted treatment strategies. With deeper elucidation and optimization of compound mechanisms, small-molecule drugs targeting succinylation modifications hold promise as novel therapeutic approaches for liver diseases. Future studies should focus on enhancing compound selectivity and specificity to advance clinical translation.

Certain natural bioactive compounds exert therapeutic effects by coordinately regulating multiple key nodes within the succinylation network, reflecting the characteristics of multi-target intervention strategies. Allicin and its metabolites are representative of such modulators, exhibiting a pronounced dose-dependent bidirectional regulatory profile (Liu et al., 2023; Li W. et al., 2022). Moderate allicin intake inhibits SIRT5 activity, upregulates uncoupling protein-1 (UCP1) succinylation in brown adipocytes, accelerates energy expenditure, suppresses lipid accumulation, and improves hepatic steatosis. Excessive allicin further inhibits SIRT5-mediated desuccinylation, leading to excessive UCP1 succinylation, inducing mitochondrial autophagy and ultimately causing morphological abnormalities and energy metabolism disorders (Zhang et al., 2020). Its active metabolite diallyl trisulfide (DATs) regulates RAB18 phase separation, upregulates CPT1A expression, promotes DLD succinylation, and induces cuproptosis in HSC (Tian et al., 2025). Thus, through the synergistic actions of the parent compound and its metabolites, allicin achieves dual regulation of the SIRT5–UCP1 pathway and the CPT1A–DLD pathway. Curcumin exerts hepatoprotective effects through multiple pathways. It inhibits ferroptosis by upregulating SIRT5-mediated desuccinylation of acyl-CoA synthetase long-chain family member 4 (ACSL4) and modulates lipid metabolism by suppressing CPT1A expression, demonstrating multi-target regulatory properties (Yashmi et al., 2024; Li R. et al., 2022; Xu et al., 2025).

The primary advantage of such multi-target modulators lies in their ability to exert more systematic and balanced regulation of the succinylation network, rather than excessive intervention at a single node, making them potentially more suitable for treating complex network-dysregulation diseases such as metabolic dysfunction-associated steatotic liver disease. However, their multi-target nature also presents challenges in elucidating mechanisms of action and optimizing clinical dosing.

Traditional Chinese Medicine (TCM) formulas exhibit unique advantages in regulating the dynamic balance of protein succinylation through multi-component synergy. Tianyang Wan (Tianyang Pill), composed of six herbs, Morinda root (Morindae officinalis Radix), Cistanche (Cistanches Herba), Cynomorium (Cynomorii Herba), processed Rehmannia root (Rehmanniae Radix Praeparata), Cornus fruit (Corni Fructus), and Chinese yam (Dioscoreae Rhizoma), can reverse the abnormally elevated global protein succinylation levels in HCC. Integrated proteomic and lysine-succinylomic analyses have demonstrated that Tianyang Wan specifically downregulates succinylation levels of key glycolytic enzymes, including PKM2, fructose-bisphosphate aldolase A (ALDOA), and LDHA, thereby suppressing the glycolytic process in cancer cells and exerting an antitumor effect (Lu, 2023). This effect suggests that the formulation exerts broad influence over the enzymatic machinery governing succinylation. Huanglian Wendan Tang (Huanglian Wendan Decoction), which contains active compounds such as quercetin and berberine, ameliorates NAFLD by synergistically modulating the CPT1A/PPARα signaling pathway to improve lipid metabolism (Zhu J. et al., 2025). Furthermore, Yiqu Gubiao Wan (Yiqu Gubiao Pill) enhances mitochondrial function and related coenzyme synthesis through upregulation of SIRT5 expression, offering a novel therapeutic approach for metabolic liver diseases (Meng, 2021) (Table 3).

The mechanisms of action of these compound formulations indicate that TCM may, through a multi-component synergistic regulatory network, systematically modulate key catalytic enzymes and substrate proteins involved in succinylation, thereby restoring metabolic homeostasis more comprehensively. This provides new research directions and material foundations for developing liver disease treatment strategies based on network modulation rather than single-target inhibition.

Despite their therapeutic promise, strategies targeting succinylation for liver disease treatment face significant translational hurdles. A primary challenge lies in achieving tissue- and cell-type-specific targeting, given the ubiquitous expression of succinylation machinery across organs. Systemic modulation risks disrupting physiological processes in non-hepatic tissues. For example, while inhibiting CPT1A may ameliorate hepatic steatosis, its broad expression in kidney, pancreas, and muscle could perturb systemic energy homeostasis (Liang, 2023). Further complicating clinical translation are narrow therapeutic windows exhibited by certain modulators. Allicin, for instance, displays a biphasic effect on SIRT5 activity; suboptimal dosing may shift outcomes from beneficial metabolic modulation to pathological disturbance (Zhang et al., 2020). Such dose-sensitive responses pose considerable challenges for clinical regimen design. Moreover, many promising natural bioactive compounds, such as quercetin and resveratrol, are hampered by unfavorable pharmacokinetic properties, including poor aqueous solubility, rapid metabolism, and low oral bioavailability. These limitations often prevent the attainment of effective drug concentrations in target tissues (Radeva and Yoncheva, 2025; Liu R. et al., 2025).

To address these barriers, advanced delivery platforms have emerged as enabling technologies. Ligand-functionalized nanocarriers enable cell-selective drug delivery to hepatocytes or hepatic stellate cells (Che et al., 2023; Jiao et al., 2025). Exosome-based systems exploit endogenous tropism for efficient siRNA delivery to specific cell populations (Xie et al., 2024). Mitochondria-directed carriers, such as those conjugated with triphenylphosphonium (TPP) or dendritic lipopeptides (DLP), significantly enhance intramitochondrial drug accumulation (Jiang et al., 2021; Chen et al., 2021). Additionally, metal-organic frameworks offer controlled release profiles through tunable porosity and surface chemistry (Liu et al., 2024d). Collectively, these innovative delivery strategies not only enhance drug bioavailability and targeting precision but also mitigate off-target liabilities, thereby providing critical support for the clinical advancement of succinylation-targeted therapeutics.

This review highlights the central role of protein succinylation in the pathogenesis of liver diseases, positioning it as a critical molecular nexus linking metabolic dysfunction, epigenetic regulation, and immune microenvironment imbalances. Although significant advances have been made in tumor biology, research on succinylation in liver pathology remains nascent. The marked sensitivity of this modification to metabolic flux and its broad capacity to regulate protein function highlights its unique research value and vast unexplored potential within the liver, which is a central metabolic organ. Thus, succinylation represents not only a potential source for developing biomarkers for liver diseases but also an important extension of therapeutic targets with significant translational medical implications.

Current research faces multiple technical bottlenecks that constrain a systematic understanding of the functional role of succinylation in liver diseases. The primary bottlenecks lie in detection and validation technologies. While advances in mass spectrometry and omics have expanded site identification, key challenges persist, including insufficient antibody specificity, analytical artifacts (e.g., neutral loss hindering site localization), a lack of robust methods for quantifying in vivo dynamics, and the loss of cell-type-specific information in bulk analyses (Azevedo et al., 2022; Hermann et al., 2022). These constraints collectively limit the functional validation of identified sites.

Beyond these technical issues, conceptual and systematic gaps remain. Mechanistic studies frequently focus on single targets, neglecting the exploration of synergistic or antagonistic networks and the crosstalk with other PTMs (Hassanzadeh et al., 2024). Furthermore, research has predominantly centered on hepatocytes, leaving the succinylation landscapes and functions in non-parenchymal cells (e.g., HSCs and Kupffer cells) poorly characterized.

To advance the field, developing detection tools with higher specificity and spatial resolution is imperative. A paradigm shift toward systems biology, integrating multi-omics and multi-cell-type analyses, is required to construct dynamic regulatory networks and fully elucidate the role of succinylation in liver physiology and disease.

Translating succinylation-targeting strategies into clinical practice presents several challenges. Although various small-molecule modulators have shown preclinical promise, their efficacy and safety lack robust support from clinical trials. It is important to note that most preclinical data are derived from rodent models, primarily mice. Significant species differences exist between mice and humans in terms of liver metabolism, immune responses, and potentially the substrate specificity or expression patterns of key succinylation enzymes (e.g., SIRT5, CPT1A) (Luo et al., 2017; Emmanuel et al., 2024). These differences may limit the direct extrapolation of therapeutic efficacy and optimal dosing from mouse models to human patients, underscoring the need for cautious interpretation of preclinical results.

Three core obstacles exist at the trial design and implementation levels: patient stratification must integrate succinylation profiles with molecular pathological features; intervention timing needs to align with disease dynamics; and efficacy evaluation requires the establishment of modification-specific biomarker systems. Furthermore, research on multi-component, multi-target TCM formulas is complicated by their unclear mechanisms of action, ambiguous active constituents, and complex pharmacodynamic foundations. To advance clinical translation in this field, a precision disease-classification system based on succinylation signatures must be established and validated through large-scale prospective cohorts for its diagnostic and prognostic value while simultaneously exploring modification-guided personalized therapies to open new avenues for the precise management of liver diseases.

Considering the current research status and challenges, future studies should achieve systematic breakthroughs across these three dimensions. Technologically, spatially resolved single-cell multi-omics technologies should be developed to enable cell-type-specific analysis of succinylation within complex hepatic microenvironments, coupled with gene-editing tools to establish high-throughput platforms for site-specific functional annotation. Mechanistically, studies must move beyond single modifications to elucidate the crosstalk between succinylation and other PTMs (e.g., acetylation and phosphorylation), thereby revealing their central roles in metabolic–epigenetic–immune networks and constructing dynamic regulatory maps. Clinically, molecular disease subtyping systems based on succinylation profiles should be advanced, modification-specific imaging probes and liquid biopsy technologies should be developed, and temporal intervention strategies targeting dynamic modification signatures should be designed to achieve personalized precision medicine.