Recent experimental evidence has shown that succinate plays multiple roles in immunity and cancer (6–8). Several studies have suggested that succinate regulates tumorigenesis in specific microenvironments (9). Succinate is often considered a traditional signal for tumorigenesis (10). However, modifications in cancer-immune cross-talk indicate that SDH may act as a tumor suppressor. According to experimental data, SDH mutations can lead to succinate accumulation and subsequent stabilization of hypoxia-inducible factor-1 alpha (HIF-1α), thereby promoting tumor growth (11) (Figure 1). M1 macrophages can produce reactive oxygen species (ROS) and inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β), which contribute to metabolic alterations and cancer-related inflammation (12) (Figure 1).

Numerous studies have shown that lipopolysaccharide (LPS)-activated macrophages can lead to succinate accumulation through inhibition of the prolyl hydroxylase domain (PHD), which further stabilizes HIF-1α, as supported by experimental evidence (Figure 1). HIF-1α, coupled with the expression of target genes encoding glycolytic enzymes and the pro-inflammatory cytokine IL-1β, can block tumor growth and survival and exacerbate inflammation (13–15) (Figure 1). Targeting the HIF-1α pathway is a promising strategy, as it plays a crucial role in attenuating liver IR injury (16). Experimental evidence has shown that the loss of activating transcription factor 3 (ATF3) exacerbates liver damage by activating the mammalian target of rapamycin (mTOR)/p70S6K/HIF-1α signaling pathway in inflammatory liver injury. Furthermore, Wang et al. have shown that deficiency of the plasma membrane-bound G protein-coupled bile acid receptor (TGR5) exacerbates hepatic IR injury by inhibiting the sirtuin 3 (SIRT3)/forkhead box O3 (FOXO3)/HIF-1α pathway (17). Therefore, current studies are identifying potential therapeutic targets via the HIF-1α pathway for the treatment of liver IR injury following LT (18). In summary, succinate may have a dual role in tumors, either promoting or inhibiting tumor growth, whereas SDH has only been identified as playing a role in suppressing tumor growth and progression.

In the context of cancer-immune cross-talk, succinate can also affect immune cells, namely antigen-presenting cells (APCs) and T cells, suggesting that targeting succinate may be a viable approach to modulating immune responses. Succinate has been shown to enhance the antigen-presenting capacity of APCs and induce an adaptive immune response that can block tumor growth, particularly in DCs (19). When stimulated by antigens, a significant increase in antigen-specific T cell activation can promote the production of cytokines such as TNF-α and interferon-gamma (IFN-γ) during immune activation (20). These cytokines can kill cancer cells and prolong the survival of patients with tumors (21, 22).

Succinate and SDH are critical for energy supply in the tricarboxylic acid (TCA) cycle of conventional metabolism. Succinate is produced by the catalysis of succinyl-CoA by succinyl-CoA synthetase (Figure 1). Immediately after the generation of succinate, it undergoes fumarate production catalyzed by SDH, accompanied by a burst of reactive oxygen species (ROS) (Figure 1). SDH is a complex consisting of four nuclear-encoded subunits. However, it is still unclear whether succinate and SDH are modulated in HCC, in contrast to a subset of cancers, especially neuroendocrine tumors, caused by SDH mutations (Figure 1).

Clinical data have shown that decreased SDH in combination with elevated succinate is associated with a poor prognosis in patients with HCC (23). In a recent biomedical study, it was revealed that SDH reduction promotes HCC proliferation by impairing the proteasomal degradation of Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) through regulation of cullin1 NEDDylation (Figure 2). Based on these findings, targeting succinate and SDH under the regulation of YAP/TAZ may provide potential therapeutic strategies for HCC (23) (Figure 2). According to research findings, aberrant S-nitrosylation sensitizes tumor cells to SDH inhibition in HCC, providing a possible molecular target in SDH for the treatment of liver cancer (24) (Figure 2). Similarly, mitophagy inhibition via the denitrosylating enzyme S-nitrosoglutathione reductase (GSNOR) leads to antitumor effects of the mitochondrial complex II inhibitor alpha-tocopheryl succinate (αTOS) (25) (Figure 2). From a clinical translation perspective, a polymer of vitamin E succinate (VES) has been designed to target tumors and enhance antitumor activity (26) (Figure 2). Many researchers have developed appropriate drug delivery systems targeting HCC cells to inhibit tumor growth and improve the efficacy of chemotherapeutic agents, even by overcoming resistance (27–32). A recent paper suggests that SDH knockdown to inactivation promotes HCC growth and metastasis via ROS/NFκB signaling (33) (Figure 2). As a key tumor suppressor metabolite, SDH provides strong evidence to support the targeting of succinate for the treatment of HCC. Regorafenib, a clinically targeted drug, plays a role in inducing cell apoptosis and promoting SDHD expression (Figure 2). SDHD is associated with cell proliferation and the therapeutic effect of regorafenib. This suggests that SDHD may be a potential drug target for HCC (34). Succinate nanocomplexes may be an effective strategy for the treatment of drug-resistant HCC based on clinical research (35) (Figure 2).

In conclusion, SDH mutations are related to the Warburg effect, also known as aerobic glycolysis, which shapes immune responses to inhibit tumor cell dedifferentiation, proliferation, and invasion in patients with HCC. Polydrugs have been designed with succinate to reverse resistance to chemotherapeutic agents. These findings suggest that targeting succinate and SDH may be a promising therapeutic strategy for HCC treatment, and further research in this area may lead to the development of more effective treatments for this disease.

IR injury is a critical factor for graft survival in organ transplantation. It is well-known that IR injury is one of the main causes of primary graft dysfunction after LT, and approximately 10% of donor livers fail due to IR injury, which also leads to a high incidence of acute and chronic rejection. Prevention of graft dysfunction may be achieved by developing new metabolites based on recent research that has implicated mitochondrial succinate metabolism in IR injury. Understanding the role of succinate and SDH in IR injury may provide insight into potential therapeutic targets for the prevention and treatment of graft dysfunction in LT. Developing new metabolites that target succinate and SDH may be a promising approach to improving graft survival and reducing the incidence of acute and chronic rejection following LT. Further research in this area is needed to identify and develop effective therapies for IR injuries in the context of LT.

Although the underlying mechanism of IR injury remains unclear, ROS production is central to IR injury in reperfused ischemic tissue - this provides new therapeutic approaches within the mitochondria as a whole (36) (Figure 2). Succinate is increased in the TCA cycle or the citric acid cycle during ischemia, and it can be catalyzed by SDH, resulting in a corresponding ROS burst during reperfusion. This, in turn, leads to calcium dysregulation and ATP depletion, which subsequently result in reperfusion injury (37). Targeting succinate metabolism opens up an impressive therapeutic strategy. Recent studies have reported that malonate can reduce IR injury during ischemia or upon reperfusion by inhibiting SDH, which is a key enzyme in cardioprotective effects in vivo (6). A possible explanation is that disruption of both succinate accumulation in ischemia and oxidation in reperfusion alters succinate metabolism (6). Succinate is selectively oxidized by mitochondria to accumulate in chronic heart failure, ischemic stroke, and renal IR injury. IR injury is mitigated by malonate therapy, which is a promising therapeutic application during LT. Disruption of succinate metabolism and modulation of SDH bridge the gap between IR injury and LT. Although many metabolites have shown promise in preventing IR injury in vitro and in vivo, translational studies have proven to be a long road from bench to bedside (6, 36).

The main technical difficulty in donor liver preservation stems, as it should, from succinate accumulation. As cold ischemia time increases during static cold storage (SCS), intracellular ATP is gradually depleted, causing mitochondrial complex II dysfunction and interruption of aerobic respiration, leading to succinate accumulation. Succinate accumulation aggravates mitochondrial complex I dysfunction, which further releases ROS and results in irreversible graft injury. Hypothermic oxygenated machine perfusion (HOPE) presents a significant improvement in recipient outcomes in ROS release and ATP depletion compared to SCS (38, 39).

In addition to succinate, acetate and itaconate provide targeted signals to regulate immunometabolism, contribute to the manipulation of IR injury, and induce immune tolerance. Acetate has explosive growth toward glycolysis in metabolic reprogramming during T cell-mediated responses (40). Glatiramer acetate, a mixture of four amino acids, has been shown to have multiple roles in immunomodulation and anti-inflammatory effects for the treatment of multiple sclerosis (MS). Surprisingly, a new comprehensive study has suggested that IR injury was attenuated by this polymeric compound in an animal model. The underlying mechanism could be elaborated via the reduction of neutrophil infiltration to alleviate tissue damage caused by IR injury (41) (Figure 2). In addition, ethyl acetate extract prevents myocardial IRI in vivo by inhibiting lipid peroxidation (42), and a recent study also showed that acetate ameliorated intestinal IRI as a novel therapeutic potential (43). In cerebral IR injury, carvacryl acetate provides neuroprotection against oxidative stress (44) (Figure 2). However, it is important to note that these results were obtained through experimental studies, and further research is needed to investigate their potential clinical applications.

Itaconate is a key immunometabolite produced by cis-aconitate from the TCA cycle in response to a variety of stimuli, such as aconitate decarboxylase 1 (ACOD1) in macrophages (45) (Figure 1). ACOD1 has been shown to suppress cerebral IR injury in mice (46). Itaconate exerts anti-inflammatory signaling by modulating macrophage metabolism and inhibiting SDH-mediated oxidation of succinate (47). Itaconate has been shown to reduce ROS production in activated M1 macrophages and is effective against cardiac, cerebral, and liver IR injuries (37, 48) (Figure 2). In the context of LT, targeting the itaconate pathway may provide an antioxidant response to inhibit liver damage from IR injury during LT (49). Hence, targeting itaconate will be considered a potential therapeutic strategy to protect the liver from IR injury and improve postoperative outcomes.

Sterol regulatory element-binding protein 1 (SREBP-1) is a ubiquitous transcription factor that activates the SREBP-1-mediated lipogenic pathway in HCC. Upregulation of SREBP-1 promotes the synthesis of fatty acids, increases cholesterol uptake into hepatocytes, and modulates mitochondrial fatty acid oxidation (FAO), according to a number of experimental studies (51–53). Moreover, high expression of the SREBP-1 protein is strongly associated with poor prognosis based on large-scale gene expression profiling (54). The suppression of SREBP-1 in HCC cells can lead to growth arrest and apoptosis, whereas overexpression of SREBP-1 promotes cell proliferation. These findings suggest that SREBP-1 could potentially be targeted for therapeutic purposes in the treatment of HCC (55) (Figure 2).

Furthermore, several microRNAs (miRNAs) mediate the pathogenesis of HCC by regulating lipid metabolism-related proteins (56–63) (Figure 2). For example, when miRNA1207-5p targets fatty acid synthase (FASN), it can inhibit HCC invasion by suppressing the protein kinase-B (Akt)/mTOR signaling pathway (57, 58). Conversely, when FASN is upregulated, it can reverse the inhibitory effects of miRNA-1207-5p on HCC cells (56, 64). Experimental research conducted by Wu et al. discovered a mechanism by which miRNA-21 contributes to the accumulation of lipids in the liver and the progression of HCC (58). This mechanism involves the interaction of miRNA-21 with the HBP1-p53-SREBP1c signaling pathway. Based on these findings, the miRNA-21-antisense oligonucleotide may be a potential therapeutic target for the treatment of HCC. In addition, miRNAs also play important roles in the regulation of lipid-metabolizing enzymes by interacting with metabolic-related transcription factors. Several miRNAs, such as miRNA-33a/b, miRNA-182, miRNA-96, and miRNA-24, have been identified as participating in the regulation of SREBPs (61–63). Studies have shown that miRNA-631 and miRNA-155 have a negative regulatory effect on liver X receptor alpha (LXRα) (65, 66). LXRα plays a crucial role in the regulation of fatty acid metabolism by controlling SREBP1-c and downstream targets involved in fatty acid synthesis (67, 68).

Downregulation of fatty acid transport protein 2 (FATP2) by knockdown or genetic deletion of FATP5 has been shown to decrease fatty acid uptake, which may have potential as a new strategy for HCC (50, 65, 69) (Figure 2). In clinical research, the expression of carnitine palmitoyltransferase 2 (CPT2), which is responsible for converting acylcarnitine back to acyl-CoA, is reduced in human steatohepatitic HCC (SH-HCC) (Figure 2). This leads to a significant accumulation of acylcarnitine species that can be detected in the serum (66). This suggests that measuring serum acylcarnitine levels may serve as a potential biomarker for HCC. More importantly, inhibition of the FAO pathway can be achieved not only by downregulation of CPT2 but also by changes in peroxisome proliferator-activated receptor (PPAR) activation (66, 70). The altered expression of PPARs mainly induces mitochondrial metabolic dysfunction, which can suppress FAO, accumulate ROS that may promote cancer cell growth, and promote lipogenesis (70) (Figure 2).

The immune responses of immune cells must change and adapt to the TME. Understanding the significant role of tumor immunometabolism reprogramming suggests a crucial targeting signal between immune cells and tumor cells, but more exploration is needed on the complex crosstalk between liver cancer cells (71). In TAMs, changes in their lipid profile are frequent. Yeung et al. (72) concluded that interactions between TAMs and HCC cells in vitro promoted tumor cell migration through M2 monocyte-derived macrophages (MDMs) in an FAO-dependent manner under IL-1β secretion (Figure 2). As for effector T cells, their activities are restricted in the TME according to recent studies (73, 74). Tumor-associated dendritic cells (TADCs) express the scavenger receptor-like macrophage scavenger receptor 1 (MSR1) to facilitate lipid uptake and accumulation in HCC (75). Increased cholesterol facilitates the antitumor effects of natural killer cells (NKs) and blocks tumor growth in vivo (76) (Figure 2). In short, future research should focus on emphasizing the underlying mechanisms of lipid metabolism in the HCC immune microenvironment.

The mTOR complex is a critical regulator of lipid metabolism and contains two distinct complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) (77, 78). Lipid metabolism is mainly controlled by mTORC1, whereas liver tumorigenesis is regulated by mTORC2 (77, 79). Therefore, many drugs targeting lipid metabolism have been developed for patients with HCC. Rapamycin, an immunosuppressant that inhibits mTOR, is widely used post-LT to regulate lipid metabolism (79, 80) (Figure 2). Rapamycin has shown anticancer potential in the treatment of HCC progression (81). Due to the synthesis and accumulation of lipids mediated by the mTOR pathway, rapamycin may cause lipid metabolism disorders after transplantation. On the one hand, rapamycin inhibits lipid storage in adipose tissue (82–86). On the other hand, it can cause lipid accumulation in the blood and liver, according to clinical data (87–90). In summary, the mTOR pathway may be a potential target to regulate immune cells by manipulating cellular lipid metabolism. Inhibition of mTOR with rapamycin can block the development of macrophages and CD4⁺ T cells in liver cancer (91, 92). Therefore, future studies should focus on combining immunity and lipid metabolism to develop novel therapeutic methods that may benefit patients with HCC.

Reversal of rejection after solid organ transplantation in vivo has been achieved by using a combination of 6-diazo-5-oxo-L-norleucine (DON), a glutamine metabolism inhibitor (97) (Figure 2). Based on experimental data, Lee et al. have shown that targeting glutamine metabolism promotes immune tolerance and leads to a good prognosis (97). Aerobic glycolysis is of crucial importance in the occurrence and development of tumors. 2-deoxy-D-glucose (2-DG), a glycolytic inhibitor, can selectively damage effector T cells by inhibiting hexokinase, which is involved in glycolysis (Figure 2). Blocking glycolysis in combination with DON and metformin [an oral hypoglycemic agent for type 2 diabetes mellitus that activates adenosine monophosphate (AMP)-activated protein kinase (AMPK), inhibits mitochondrial respiratory complex I of the electron transport chain (ETC), and promotes FAO] prevents graft rejection in solid allograft transplantation models (98) (Figure 2). It is worth noting that metformin attenuates ischemia-reperfusion (IR) injury in fatty liver disease via the toll-like receptor 4 (TLR4)/NF-κB axis (99). Preconditioning with metformin also lowers hepatobiliary injury and improves hepatobiliary function in an in situ and ex-situ model of rat donor LT (100). Chen et al. have shown that methylcrotonoyl-CoA carboxylase 2 (MCCC2) correlates with the leucine metabolism pathway in the progression of HCC and may be a new target for HCC (101) (Figure 2). The branched-chain amino acids to tyrosine ratio can predict the prognosis of HCC treatment based on clinical practice data (102). Solute carrier family 27 member 5 (SLC27A5) and tyrosine metabolizing enzymes identified by Wang et al. coordinate lipid and tyrosine metabolism in HCC, alter the tumor cell cycle, and are potential targets for cancer treatment (103) (Figure 2).