Iron–sulfur cluster proteins are a kind of protein cofactors that modulates various biochemical processes, including mitochondrial respiration, electron transfer, redox catalysis and biosynthesis (13, 14). The human genome contains two homologous ferredoxins, ferredoxin 1 (FDX1) and ferredoxin 2 (FDX2). FDX1 produces a market effect on steroidogenesis, while FDX2 is involved in the synthesis of Fe -S cluster and heme A (15).

One of the signs of cancer is cellular metabolism disorders (16). It happens that the main function of FDX1 is to regulate substance metabolism. Hence, researchers have explored the association between FDX1 and cancer. Downregulation of FDX1 significantly changes glucose, amino acid, and fatty acid oxidative metabolism in lung adenocarcinoma. Meanwhile, the prognosis of lung adenocarcinoma patients with low expression of FDX1 is even worse (17). This is consistent with the previous studies.The most common manifestation of lung cancer metabolism is abnormal glucose and lactic acid metabolism (18). Besides, the steroid synthesis regulated by FDX1 may be related to the occurrence of tumors. FDX1 is involved in regulating steroid hormone synthesis, receiving electrons transferred from NADPH via Adx reductase, which in turn reduces members of the mitochondrial cytochrome P450 (CYP450). CYP450 mainly includes CYP1, CYP2 and CYP3 families. CYP1B1 in the CYP1 family catalyzes the conversion of estradiol to 4-hydroxy-17-β-estradiol (4-OHE2) (19). The metabolite of estradiol,4-OHE2, is involved in the development of some hormone-related cancers. For example, 4-OHE2 undergoes the redox cycle, which produces reactive oxygen species (ROS) and chemoreactive estrogen semiquinone, thereby promoting the occurrence of breast cancer (20). In endometrial cancer, 4-OHE2 participates in the occurrence of endometrial cancer by inducing PTEN mutation on codon 130/131 (21). So the potential association between FDX1 regulating CYP450 and the pathogenesis of hormone-related cancer deserves further study. From this, we speculate FDX1 may be involved in the metabolic disorder during the occurrence and development of cancer, subsequently changing its phenotype and tumor microenvironment.

With the proposal of cuproptosis, a research conducted systematic bioinformatic database analysis on FDX1. Firstly, the expression of FDX1 at mRNA and protein levels was reduced in most cancers, such as breast invasive carcinoma (BRCA), colon adenocarcinoma (COAD), lung adenocarcinoma (LUAD), thyroid carcinoma (THCA), etc. Secondly, the expression of FDX1 was related to the clinical features, anti-tumor drug sensitivity and drug resistance in some cancer types.Simultaneously, gene-set enrichment analysis showed tight correlation between FDX1 and immune-related pathways, immune cell infiltration, and immunoregulatory genes (22). Although the analysis of public bioinformatic database has some limitations due to the limited clinical and pathological information, it also indicates FDX1 is expected to become a potential target for cancer treatment and a biomarker for evaluating prognosis in the future.

Lipoic acid is an antioxidant synthesized in mitochondria. It can not only clear free radicals,but also participate in regulating mitochondrial energy metabolism and oxidative stress. Lipoic acid synthase (LIAS) belongs to the biotin and lipoic acid synthase family, which is involved in catalyzing the final step of lipoic acid synthesis (23). Relevant studies have shown the lower expression of LIAS can promote the progression of diseases such as diabetes, atherosclerosis and neonatal epilepsy by increasing oxidative stress (24–26). Downregulating LIAS by RNA interference may lead to redox imbalance, mitochondrial dysfunction and inflammation (27). As a result, LIAS is related to mitochondrial energy metabolism and antioxidant defense. Mitochondria participate in electron chain transfer and oxidative phosphorylation through TCA cycle. Some tumors with high level of oxidative phosphorylation (such as breast cancer, melanoma, cholangiocarcinoma, etc) are mainly powered by it.Studies have applied drugs targeting oxidative phosphorylation such as PGC-1α to inhibit the proliferation of tumor cells (28–30). Therefrom, we surmise LIAS may become a latent therapeutic target for mitochondrial respiration-dependent tumors. Moreover, experiments have proved the mutation of LIAS inhibits the activity of proline hydroxylase (PHDs), thereby promoting the activation of HIF-1 (31). It is universally acknowledged that the higher expression of HIF-1 is a prerequisite for tumor cell proliferation and migration, angiogenesis and epithelial-mesenchymal transition (EMT) (32). Consequently, LIAS may have an effect on tumor proliferation and invasion by regulating HIF-1. Finally, the effect of LIAS on oxidative stress and inflammation provides clues to its role in tumor immunotherapy. In the atherosclerotic mouse model with the overexpression of LIAS, it was found that the number of Treg was increased and T cell infiltration was reduced (25). Similarly,in pulmonary fibrosis mice with the overexpression of LIAS, the inhibition of NF-kB relieved the chronic inflammatory response, showing an increase in the number of Treg cells and a decrease in T cell infiltration (33). The latest pan-cancer analysis of the bioinformatics database on LIAS is consistent with the above experimental conclusions. Researchers found the expression of LIAS was correlated with the infiltration of immune cells (34). In the tumor microenvironment, increased Treg cells will inhibit the activation and function of effector T cells, resulting in the immune escape of tumor cells (35). In conclusion, LIAS may have far-reaching effect on the proliferation, angiogenesis and immune escape of tumor.

Pyruvate dehydrogenase complex (PDC) is a multienzyme complex located in mitochondria that catalyzes pyruvate, transfers acetyl groups to coenzyme A through DLAT, finally transforms to acetyl-CoA. DLAT is the E2 subunit of PDC complex, which is critical to TCA cycle (36). So far, a series of studies have demonstrated the role of DLAT in tumors. Wen et al. (37)observed the expression of DLAT was appreciably upregulated in gastric cancer cells, which promoted oxidative phosphorylation and provide energy for tumor cells by catalyzing the conversion of pyruvate to acetyl-CoA. Shan et al. (38) found DLAT promoted tumor cell proliferation and growth by elevating the level of 6PGD lysine acetylation in primary leukemia. According to the research on non-small cell lung cancer, PM2.5 upregulated the expression of DLAT to promote glycolysis through the dual regulation mechanism of Sp1-DLAT and eIF4E-DLAT axis, enhancing the proliferation of tumor cells (39).

Next, we have noticed the association between E4F1 and tumors, which is involved in the modulation of PDC subunits.E4F1 was initially identified as a cellular target of the viral oncoprotein E1A. It regulates DLAT transcription to control the metabolism of pyruvate oxidation pathway (40). Most importantly, E4F1 mediates the ubiquitination of tumor suppressor gene p53, enhancing its transcriptional activity and eventually arresting the cell cycle (41). Accordingly, E4F1 may affect the development of cancer by coordinating p53 and DLAT.

Finally, DLAT is a biological substrate of Sirtuin 4 (SIRT4) lipoamidase activity. SIRT4 induces DLAT hydrolysis to regulate TCA cycle by lipoyl- and biotinyl-lysine modifications of DLAT ( 42). According to the classical theory “Warburg effect”, most tumor cells obtain energy through aerobic glycolysis. It is considered to be a marker of cancer progression and metastasis (43). It was found that the glycolysis was decreased in overexpressing SIRT4 hepatocellular carcinoma (HCC) cell lines. In other words, the overexpression of SIRT4 will reduce the energy obtained by the tumor (44). To sum up, DLAT may influence tumor development by regulating pyruvate oxidation, TCA cycle and glycolysis.

CTR1 is a high-affinity copper transporter encoded by SLC31A1. The C terminus of CTR1 is intracellular and the N terminus is extracellular. It is arranged in the form of homotrimer on the cell membrane to facilitate the inflow of copper. In the pregnant mouse model with the deficiency of CTR1, obvious growth and development defects was discovered in embryo. Even worse, some embryos would die in utero in the secong trimester of pregnancy. This demonstrates CTR1 is crucial in embryonic development (55).

Actually, studies have shown CTR1 is highly expressed in melanoma, liver cancer, prostate cancer and other human cancer cell lines (56). Subsequently,many reports investigate the effect of CTR1 on tumor progression from tumor-related signaling pathways, angiogenesis and platinum drug resistance. First and foremost, CTR1 mediates copper causing cell signal cascade disorder indirectly, which leads to the occurrence and development of tumors. Abnormal activation of mitogen-activated protein kinases (MAPK) signaling is a classic hallmark of several malignant tumors. The mutation of RAS and BRAF is the most common (57). In 2014, Counter Research Group (9)confirmed downregulating the expression of CTR1 may influence the combination of MEK1 and copper, thereby inhibiting ERK signaling pathway mediated by BRAF and ultimatingly suppressing the tumor growth. In other words, copper modulated by CTR1 regulates BRAF/MEK/ERK signaling pathway indirectly.

Secondly, angiogenesis is the initial process of tumor proliferation and metastasis (58). Earlier studies have indicated copper is a vital element in promoting angiogenesis. It can not only activate the main factors of angiogenesis by HIF-1, but also combine with angiogenin to promote angiogenesis (59). In human umbilical vein endothelial cells (HUVECs), the downregulation of CTR1 prevented copper from entering vascular endothelial cells and reduced angiogenesis (60). Another experiment is in line with the above conclusion. Three peptides rich in histidine and methionine are designed in the copper-binding region of CTR1, preventing copper from entering cells and inhibiting angiogenesis (61). Hence,the inhibition of CTR1 causing unbalanced copper may become a new idea for anti-angiogenesis.

Last but not least, studies have deeply explored the relationship between chemoresistance to cisplatin and the expression of CTR1. Platinum drugs are one of the most common chemotherapeutic agents for many solid tumors. Resistance of tumor cells to cisplatin is the key reason for the poor effect of chemotherapy. Studies have revealed CTR1 is the major transporter of platinum drugs (62). In addition, patients who had received platinum chemotherapy with stage III non-small cell lung cancer were selected to study their tumor tissues by immunohistochemistry experiments. The results indicated the high expression of CTR1 had a better response to cisplatin treatment and favourable prognosis (63). In human ovarian cancer cells, cisplatin downregulated the levels of CTR1 in time- dependent and concentration-dependent manner (64). Apparently, CTR1 has the potential to be a new target to overcome platinum resistance.

ATP7A and ATP7B are two homologous isoforms of copper-transporting P-type ATPases. In order to expel excessive copper from the body, ATP7A transports copper to the basement membrane of extracellular matrix, while ATP7B transports it out of hepatic cells and into bile. The mutation of ATP7A and ATP7B will damage the nervous system, leading to Menkes disease and Wilson disease respectively (65). Additionally, ATP7A and ATP7B also produce a marked effect in tumor progression. First, The members of LOX family modulates extracellular matrix (ECM) remodeling leading to tumor cell migration (66). According to a study applying CRISPR/Cas9 to silence ATP7A,the activity of LOX was inhibited in breast cancer and lung cancer cell lines,suppressing these tumor cell growth and migration (67). Meanwhile, KRAS-mutant colorectal cancer obtained high levels of copper through pinocytosis accompanied by the upregulation of ATP7A ( 68). Furthermore, The combination of ATP7A and VEGFR2 can prevent the degradation of VEGFR2 to promote angiogenesis through P62-SQSTM1 pathway (69). It is noteworthy ATP7A or ATP7B can bind to platinum drugs to expel it from cancer cells, producing chemotherapy drug resistance. In breast cancer cell MDA-MB-231 with ATP7A knocked out, the ability of cisplatin to reduce cell proliferation was enhanced. This study indicated the overexpression of miR-148a-3p negatively regulates ATP7A, which will increase the sensitivity of breast cancer cells to cisplatin (70). Similarly, targeting ATP7B negatively regulated by miR139 will reduce the chemical resistance of ovarian cancer cells to platinum drugs (71). In conclusion, targeting Copper-transporting ATPases,ATP7A or ATP7B,has broad application space in overcoming the resistance of tumor cells to platinum drugs.