Copper is an important trace element that plays a significant role in many biological processes, including cell respiration, cell proliferation, antioxidant defense, neurotransmitter synthesis and angiogenesis. Wilson’s disease, Alzheimer’s disease, and Parkinson’s disease have been associated with an abnormal copper metabolism (28, 29). Normal life activities rely heavily on copper homeostasis being maintained. The liver plays a crucial role in controlling systemic copper homeostasis. Copper is absorbed in the intestine to fulfill the body’s needs, and excreted through the bile to prevent toxicity. Cu transporting ATPase B (Atp7b) in hepatocytes assists secreting excess copper, which will be excreted with bile (28). In humans, mutations in the Atp7b gene are responsible for Wilson’s disease, a disorder that produces hepatic copper overload comparable to copper toxicosis in dogs. Exon 2 deletion of COMMD1 in Bedlington Terriers results in the loss of COMMD1 protein expression, which ultimately results in aberrant biliary copper excretion and copper toxicosis (30). However, the mechanism by which COMMD1 regulates biliary copper excretion remains unknown. Studies have demonstrated that COMMD1 could bind to mutant Atp7b and promoted its degradation via the proteasomal pathway (31). Researchers speculated that COMMD1 is involved in the quality regulation of Atp7b through hydrolyzing misfolded and dysfunctional proteins caused by mutations. Failure to properly regulate Atp7b in Bedlington Terriers due to COMMD1 deficiency may be the underlying cause of copper toxicosis (32). Copper is efficiently secreted due to the bidirectional translocation of Atp7b between trans-Golgi network and cytosolic vesicles. Miyayama et al. discovered that COMMD1-knockdown decreased the expression of Atp7b; concurrently, the recycling of Atp7b from cytosolic vesicles to the trans-Golgi network is hindered, resulting in the accumulation of intracellular copper (33). The majority of dietary copper is absorbed in the small intestine, and Atp7a transports copper from small intestine cells to the portal vein. A mutation in the Atp7a gene could cause Menkes’ disease, which is mostly characterized by copper deficiency (28). COMMD1 could bind to both wild-type and mutant Atp7a, increasing Atp7a’s stability and ameliorating the copper exporting capacities of Atp7a mutants (34). In contrast, another research published in the same year shown that COMMD1 triggered the degradation of wild-type and mutant Atp7a through proteasomal pathway (31). The role of COMMD1 in the stability of Atp7a requires additional study. COMMD1 can also regulate the intracellular transport of Atp7a. COMMD1 forms the COMMD/CCDC22/CCDC93 (CCC) complex with CCDC22, CCDC93, and C16orf62, which is necessary for the proper sorting and relocalization of Atp7a (4, 35). COMMD1 can directly bind copper in addition to interacting with Atp7a and Atp7b. However, the importance of this binding effect on copper homeostasis is unexplored (36). There is no indication that COMMD1 gene mutation induces human copper metabolic-related disorders such as Wilson’s disease, while numerous pieces of evidence indicate that COMMD1 is involved in the regulation of copper metabolism. Also, the role of COMMD2-10 in regulating copper metabolism is rarely explored. It has been observed that the deletion of any one of COMMD1, COMMD6, or COMMD9 leads to a deficiency in the transport of Atp7b from cytosolic vesicles to the plasma membrane in mouse hepatocytes, and a hepatic copper accumulation in conditions of a high-copper diet (37). The function of the COMMD protein family in copper homeostasis requires additional investigation.

Receptor endocytosis and subsequent sorting is an important way to maintain cell homeostasis. Early endosomes internalize transmembrane proteins and their associated macromolecules, some of which degrade through the lysosomal pathway while others are transported to trans-Golgi network or plasma membrane for reuse by retromer, retriever, WASH complex, CCC complex, and SNX proteins (38). Phosphatidylinositol 4, 5-bisphosphate (PtdIns (4, 5) P₂) is an important membrane-anchoring molecule, functioning in vesicular trafficking and modulation of transporter activity. The specific binding of COMMD1 to PtdIns(4, 5)P₂ makes COMMD1 recruited to the endocytotic membranes, where it functions in endosomal sorting (39). Subsequent investigations demonstrated that COMMD1’s endosomal sorting role is performed through the formation of the CCC complex. Depletion of COMMD1 or CCC complex inhibits the transfer of Atp7a from endosomal vesicles to the plasma membrane. CCC complex binds to the WASH complex member FAM21, and CCC complex, WASH complex, and retromer are all implicated in the regulation of endosomal trafficking of Atp7a (35). The low-density lipoprotein receptor (LDLR) plays significant role in eliminating low-density lipoprotein (LDL). CCC and WASH complexes are both involved in the endosomal sorting of LDLR to maintain the homeostasis of circulating cholesterol. Similar to COMMD1, COMMD6-knockout and COMMD9 in mouse hepatocytes also destabilizes the CCC complex, resulting in reduced LDLR levels on the cell surface and elevated plasma cholesterol (40, 41). Another research conducted in the same year indicated that COMMD9 is also a component of the CCC complex and is essential for the endosomal sorting of Notch receptors. Given that almost all members of the COMMD protein family can connect with the CCC complex component CCDC22 (40), it is hypothesized that the various COMMD proteins associated with the CCC complex aid in the specific cargos selection (42). Unlike Atp7a, the endosomal cargo recycling of α₅β₁-integrin is retromer-independent. Retriever interacts with cargo adaptor SNX17 and combines CCC and WASH complex to facilitate cell surface recycling of α₅β₁-integrin (43). In conclusion, CCC complex and related proteins play an important role in the endosomal sorting of transmembrane receptors.

ENaC is an amiloride-sensitive Na⁺ channel, and is comprised of three homologous subunits (α, β, and γ; or δ, β, and γ), which plays a significant role in Na⁺ and body fluid volume homeostasis (44). COMMD1 interacts with Nedd4-2 to increase the ubiquitination and promote the degradation of ENaC (α, β, and γ) (45). In addition, COMMD1 was also found able to bind to δENaC, therefore promoting δENaC into an intracellular recycling pool and reducing δENaC on the cell surface while enhancing ENaC ubiquitination. However, it is unknown if Nedd4-2 is involved in the regulation of δENaC (46). Additionally, COMMD2-10 interacts with ENaC, and later investigations on COMMD3 and COMMD9 have shown that they both lower ENaC expression on the cell surface and amiloride-sensitive current in mammalian epithelia. The COMMD protein family appears to play a negative regulatory role on ENaC (47). However, COMMD10-knockdown in Fischer rat thyroid epithelia resulted in increased Nedd4-2 and decreased ENaC current. In conclusion, COMMD1 inhibits Na⁺ transport by promoting ENaC ubiquitination and endocytosis; nevertheless, the regulatory mechanism of COMMD on ENaC proteins and its subunits need more investigation. In epithelial tissue, the cystic fibrosis transmembrane conductance regulator (CFTR) is a vast polytopic cAMP-regulated Cl^- channel. Overexpression of COMMD1 in Hela cells increased the amount of CFTR on the cell surface, while COMMD1-knockdown induced ubiquitination and probably proteasomal degradation of CFTR (48). The Na-K-Cl co-transporter 1(NKCC1), a member of the cation-Cl cotransport family, interacts with COMMD1 to ubiquitinate itself, hence enhancing its own expression in the basolateral membrane. One potential reason is that COMMD1 improves the biological activity of NKCC1 by promoting non-classical ubiquitination, which stabilizes rather than degrades the target protein (4, 49).

The NF-κB family is an essential transcription factor that regulates the expression of several genes and participates in a variety of physiological processes, such as immune response, inflammation, and cell survival. RelA(p65), RelB, cREL, NF-κB1(p50/p105), and NF-κB2(p52/p100) occur as homodimers or heterodimers in cells as five members of the NF-κB family. Furthermore, the NF-κB family members in inactive status bind to inhibitor of NF-κB (IκB) (7, 50). In the canonical NF-κB pathway, PAMPs/DAMPs (such as LPS and CpG DNA), proinflammatory cytokines, and other stimulations, activate the receptors on the cell membrane. IκB is subsequently phosphorylated by IκB kinase (IKK) and degraded by proteasomes. RelA/p50 dimers that are no longer inhibited by IκB translocate to the nucleus to bind DNA and mediate transcription (50). In the majority of instances, all ten COMMD proteins may bind selectively to distinct subunits of NF-κB and inhibit the activity of NF-κB (6, 51)( Figure 2 ). COMMD1 is the most well investigated regulator of the NF-κB signaling pathway. COMMD1 interacts with ECSSOCS1, a multimeric E3 ubiquitin ligase complex composed of Elongins B and C, cullin2, and SOCS1, in order to increase RelA binding to SOCS1, resulting in the ubiquitination and proteasomal degradation of RelA, hence inhibiting NF-κB-mediated transcription (52). RelA Ser468 phosphorylation induced by IKK is required for COMMD1-dependent ubiquitination of RelA (53, 54). The phosphorylation of RelA at Ser468 increases its binding to general control non-repressed protein 5(GCN5), which forms a complex with COMMD1 and ECSSOCS1, increasing RelA ubiquitination and degradation (54). Notably, COMMD1 continues to occupy the promoter site even after RelA is removed, indicating that COMMD1 may inhibit the expression of NF-κB target genes by this method (53). In addition, COMMD1 overexpression inhibits NF-κB-mediated transcription by decreasing the binding time of RelA to chromosomes (6) and IκB ubiquitination (51, 55). Acetylated COMMD1 in the cytoplasm induced the nucleolus translocation of RelA to mediate apoptosis by ubiquitylating RelA (56). Acetylated COMMD1 ubiquitinates RelA. Ubiquitinated RelA translocates to the nucleus to mediate apoptosis. CCDC22, a highly conserved protein associated with X-linked intellectual disability, binds to COMMD proteins in conjunction to regulate the NF-κB signaling pathway. Cullin1 interacts with the CCDC22-COMMD8 complex to enhance IκB ubiquitination and NF-κB-mediated transcription. In contrast, the CCDC22-COMMD1 complex binds Cullin2 in order to promote RelA ubiquitination and inhibits the NF-κB pathway. Given that CCDC22 deficit inhibits NF-κB activation, the CCDC22-COMMD8 complex may serve as the primary regulator (57). Reportedly, COMMD7 enhances the activation of the NF-κB signaling pathway in HCC, which will be described in depth in the next section of this review (58).

Superoxide dismutase 1(SOD1), a member of the Cu,Zn superoxide dismutase family, catalyzes the production of molecular oxygen and hydrogen peroxide from superoxide anions, therefore acting as an antioxidant. Homodimer formation is the last stage in SOD1 maturation, and COMMD1 may decrease the amount of SOD1 homodimers, hence inhibiting SOD1 maturation and activity (59). Also regulated by COMMD1 is the hypoxia inducible factor 1 (HIF-1). Overexpression of COMMD1 promotes the degradation of HIF-1α, while COMMD1 deficiency raises the stability of HIF-1α, increasing the transcription of HIF-1α target genes, and resulting in developmental defects and embryonic lethality (60). On the one hand, COMMD1 competitively inhibits Heat Shock Protein 90 (HSP90), which binds to and stabilizes HIF-1α. On the other hand, after binding to HIF-1α, COMMD1 cooperates with Heat Shock Protein 70(HSP70) to induce the ubiquitin-independent degradation of HIF-1 (61). In addition, COMMD1 may directly inhibit the formation of HIF-α and HIF-β to heterodimers with transcriptional activity (62). In a recent investigation on hepatocellular cancer, COMMD10 was also discovered to bind and inhibit HIF-1α (63), and it has to be determined if additional members of the COMMD protein family have comparable effects. Additionally, the COMMD prtotein family may engage in cell cycle control. Overexpression or silencing of COMMD1 in HEK293T cells regulates the cell cycle and cell proliferation via altering the level of p21 Cip1 (64). The interaction between Lamin A and COMMD1 indicates that COMMD1 may potentially be associated with aging and laminopathies (65). Many investigations have shown that the COMMD protein family is broadly involved in physiological processes, including copper metabolism, endosomal sorting, ion transport, transcriptional control, and others; nevertheless, the probable molecular mechanism remains unexplored.

Lung cancer is a leading cause of cancer-related mortality, with roughly 85% of cases attributable to smoking (which is also affected by other environmental factors). Lung cancer is separated histologically into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC); NSCLC includes adenocarcinoma (ADC), squamous cell carcinoma (SCC), and large cell carcinoma (undifferentiated NSCLC), accounting for over 80% of lung cancer cases and causing over 1.2 million deaths annually. Despite the widespread use of surgery, radiotherapy, chemotherapy, targeted therapy, and other treatments for the treatment of lung cancer, the prognosis of patients remains dismal, and the 5-year overall survival rate is just 15% (66, 67). By upregulating genes associated to cell proliferation, metastasis, angiogenesis, and anti-apoptosis, NF-κB may contribute to oncogenesis. It is believed that aberrant activation of the NF-κB signaling pathway promotes tumor survival and medication resistance by upregulating anti-apoptotic proteins and genes (67, 68). Given the obvious inhibitory effect of the COMMD protein family on NF-κB, it is plausible to hypothesize that COMMD proteins play a crucial role in oncogenesis, progression, and death. CIGB-552 is a synthetic anti-tumor peptide that stimulates the ubiquitination of RelA, a subunit of NF-κB, in lung cancer cells, therefore decreasing the anti-apoptotic action of NF-κB and promoting the death of tumor cells. The protein-protein interaction between COMMD1 and CIGB-552 and the accumulation of COMMD1 were also observed in lung cancer cells influenced by CIGB-552. Further research revealed that the COMMD1 knockout inhibited CIGB-552-induced NF-κB degradation and cell death. Therefore, COMMD1 upregulation produce antitumor effects through inhibiting the NF-κB signaling pathway (68). HIF-1 is another COMMD1-regulated transcription factor, and is involved in energy metabolism, cell growth, and angiogenesis. Similar to NF-κB, CIGB-552 promotes COMMD1 accumulation and inhibits HIF-1 activity in H460 cells (69), hence exerting anti-inflammatory and anti-angiogenic actions. CIGB-552 and cisplatin performed a synergistic impact in inhibiting tumor cell growth, inducing apoptosis and oxidative stress response, and overcoming cisplatin resistance in a recent research involving lung cancer cells and mice models (70). It is worth noting that COMMD1 promoted the repair of DNA double-strand breaks (DSBs) in lung cancer cells. The research also revealed that the upregulation of COMMD1 increased the proliferation of NSCLC cells and was associated with a bad prognosis for patients. Even COMMD1-knockdown might increase the radiation sensitivity of NSCLC cells (17). As a potential novel anticancer treatment target, the function of COMMD1 in NSCLC requires additional investigation. In addition to COMMD1, additional COMMD protein family members have showed promise as prospective lung cancer therapeutic targets. Compared to healthy tissues and cells, the gene and protein expression levels of COMMD4 is upregulated in NSCLC, and patients with high COMMD4 expression are more likely to have a poor prognosis. COMMD4 depletion significantly inhibits NSCLC cell growth, induces mitotic catastrophe and death, and increases NSCLC sensibility to irradiation and camptothecin. Because irradiation and camptothecin might produce DNA DSBs, COMMD4 activity is crucial for protecting NSCLC cells from DNA damage (18). COMMD8 is up-regulated in NSCLC, and COMMD8 promoted cell proliferation, migration, glycolysis and inhibited cell apoptosis in NSCLC. In addition, research have shown that COMMD8 might be activated in NSCLC through activating MALAT1/miR-613 axis and LINC00657/miR-26b-5p axis, playing a carcinogenic role (19, 71). In NSCLC cells, DRTF1 and E2F1 join to create a heterodimer in order to enhance G1/S transition and inhibit P53 activity. The high expression of COMMD9 in NSCLC increases cell proliferation and invasion. COMMD9-knockdown results in G1/S arrest, induces autophagy, inhibits the activation of TFDP1/E2F1 and enhances P53 signaling pathway, playing an antitumor effect (20).

Hepatocellular carcinoma (HCC) is the most prevalent type of primary liver cancer and the third biggest cause of cancer-related mortality globally. In recent years, several studies have shown that the COMMD protein family plays a crucial role in the development and incidence of HCC. Analysis of bioinformatic data revealed that COMMD2 was highly expressed in HCC and promoted the proliferation and migration of HCC cells, making it a potential oncogene. A high expression of COMMD2 is associated with poor prognosis, higher histological grade, more advanced clinical stage, lymph node metastasis and the TP53 mutation status in HCC patients. Additionally, COMMD2 impacts the overall survival of patients with HCC by enhancing tumor immune infiltration (21). Similarly with COMMD2, COMMD3, COMMD7, and COMMD8 are overexpressed in HCC, increasing cell proliferation, migration, and invasion (22, 24, 58). In HCC patients, COMMD3 upregulation is related with advanced TNM stage, poor overall survival, and vascular invasion. In null mice with subcutaneous xenograft tumors, silencing COMMD3 inhibited tumor development and expression of HIF1α, VEGF, and CD34. In HCC, COMMD3 seemed to operate as an upstream regulator of HIF1α (22). Several investigations have elaborated on the involvement of COMMD7 in HCC, despite the fact that COMMD7 inhibits NF-κB activation in HEK293T cells (72). Instead, COMMD7 stimulated NF-κB in HCC cells. A positive feedback loop was formed when COMMD7 silencing induces HCC cell apoptosis by inhibiting NF-κB, and inhibited NF-κB further lowerd COMMD7 transcription. Researchers suggested that the inconsistent action of COMMD7 on NF-κB might be due to the different cell types or cytokine stimulation (73, 74). COMMD7 overexpression alone activated NF-κB signaling pathway by increasing PIAS4-mediated NEMO sumoylation in Nanog⁺ HCSCs, but the overexpression of COMMD1 and COMMD7 together ended NF-κB signaling (58). Moreover, overexpression of COMMD7 in HCC might increase cell proliferation and invasion by promoting ROS accumulation and activating NF-κB, and downstream CXCL10 (23, 75). COMMD10, unlike COMMD7, inhibits HCC cell proliferation by inhibits the NF-κB signaling pathway and enhances cell death by activating the signaling pathway of Bcl‐2/Bax/caspase-9/3. On the on hand, COMMD10 binds to the Rel homology domain of p65 in HCC cells and inhibits the nuclear translocation of NF-κB. On the other hand, COMMD10 reduces the ubiquitination and degradation of IκB, hence reducing the action of NF-κB (25). Another research revealed that COMMD10 increased radiosensitivity in HCC cells by decreasing intracellular Cu, inhibiting HIF1α, and stimulating ferroptosis (63). COMMD10 exhibits an anticancer impact in HCC and is related with increased survival.

Similar to the effect in lung cancer, COMMD1 exerts an anti-tumor effect in malignant tumors, including prostate cancer (76), diffuse large B-cell lymphoma (77), head and neck squamous-cell carcinoma (HNSCC) (78), and neuroblastoma (79). Downregulation of COMMD1 was related with a poor prognosis for diffuse large B-cell lymphoma, according to bioinformatics study (77). COMMD1 decreases tumor cell activity by inhibiting the NF-κB signaling pathway in prostate cancer and neuroblastoma (76, 79). COMMD1 increases its stability by forming a complex with DRR1 and F-actin in the nucleus of neuroblastoma. Subsequently, DRR1 and COMMD1 inhibits cyclinD1 expression, the G1/S transition, and neuroblastoma cell proliferation (79). miR-205 enhances inflammatory and stemness properties in stemness-enriched HNSCC cells and promotes tumorigenesis and tumor progression via downregulating COMMD1. COMMD1 downregulation also enhances the activation of NF-κB in HNSCC cells, which in turn promotes the release of inflammatory factors into the tumor microenvironment and further increases miR-205 expression (78). HIF-1, a transcription factor, is similarly regulated by COMMD1 in tumor cells. In HT29 and U2OS cells, reduced COMMD1 expression inhibits many HIF-responsive genes, including VEGFA, TGFA, HK2, and GLUT1. Notably, COMMD1-deficient tumor cells did not exhibit an increase of protein level in HIF-1α or HIF-2α. Further research demonstrated that COMMD1 bond to HIF-1α in a competitive manner and prevented the formation of the HIF-1α/β heterodimer (62), hence inhibiting the DNA binding and transcriptional activity of HIF-1α. Furthermore, COMMD1 is associated to drug resistance in ovarian cancer and multiple myeloma (26, 80). Ovarian cancer cells A2780 are more susceptible to cisplatin when nuclear COMMD1 expression is increased. The mechanism might include COMMD1’s regulation of the G2/M checkpoint, DNA repair, and apoptosis (26). In Bortezomib-resistant multiple myeloma, however, COMMD1 expression was shown to be elevated. By inhibiting SCF complex, COMMD1-knockdown could overcome Bortezomib resistance (80). By activating COMMD1, CIGB-552 reduced the growth of breast cancer cells MCF-7 and colon cancer cells HT-29 in addition to lung cancer cells (81). Gene rearrangement is often linked with an aggressive phenotype and poor prognosis in prostate cancer. The researchers discovered that COMMD3: BMI1 fusion expression was significantly elevated in metastatic prostate cancer. COMMD3 activates oncogenes such as c-MYC, which promotes prostate cancer cell proliferation, migration, and invasion; COMMD3 expression is positively connected with tumor recurrence and decreased survival rate (82). COMMD5, also known as hypertension-related, calcium-regulated gene (HCaRG), is strongly expressed in renal proximal tubules, where it regulates cell proliferation and differentiation, and accelerate the repair of renal tubules. However, excessive proliferation and poor differentiation are significant tumor progression indicators. In renal cancer cells, COMMD5 decreases proliferation, improves differentiation, accelerates autophagic cell death, and lowers VEGF production through downregulating HIF-1α, ultimately inhibiting tumor angiogenesis. The overexpression of ErbB receptors (including EGFR, ErbB2, ErbB3, and other receptors) is related with the development and progression of cancer, and have been observed in several epithelial-derived human malignancies. In renal cell cancer, COMMD5 inhibits the methylation of EGFR and ErbB3 promoters. COMMD5 significantly reduces the transcription and translation of EGFR and ErbB3 by inhibiting the methylation of EGFR and ErbB3 promoters, ultimately performing an antitumor function (83, 84). Expression of COMMD5 is reduced in gastric cancer. Rosiglitazone, a synthetic PPAR agonist, was associated by COMMD5 up-regulation in inhibiting gastric carcinogenesis, according to studies. However, the precise function of COMMD5 in gastric cancer requires additional investigation (85). In pancreatic ductal adenocarcinoma (PDAC) (86) and acute myeloid leukemia (87), high COMMD7 expression is associated with a poor prognosis. COMMD7 is positively linked with PDAC histological differentiation, lymph node metastasis, and TNM staging. By downregulating cyclin D1, inhibiting MMP-2 secretion, and activating the ERK1/2 and apoptosis signaling pathways, inhibition of COMMD7 may reduce tumor growth and invasion (86). Additionally, COMMD7 is connected with medication resistance. In gastric cancer, the activation of the Linc00852/miR-514a-5p/COMMD7 axis enhances cisplatin resistance (88). Loss of ETV6 function is associated with the development of hematological cancers. Using a functional genome-wide shRNA screen, researchers discovered that COMMD9-knockdown in leukemic cells might inhibit ETV6 transcriptional activity (89). However, the underlying mechanism by which COMMD9 regulates ETV6 remains unknown. Formin-like2 (FMNL2) is a member of the Formins family, which is upregulated in colorectal cancer and increases tumor cell motility, invasion, and metastasis (90). Additional research demonstrated that FMNL2 enhanced the ubiquitin-mediated proteasome degradation of COMMD10, hence reducing the nuclear translocation of NF-κB subunit p65 and promoting tumor progression. COMMD10 downregulation is often correlated with worse clinical outcomes. Consequently, COMMD10 may be employed as an independent survival predictive marker for CRC patients (91). Bioinformatics analysis revealed that the expression of COMMD10 in lung squamous cell carcinoma, breast invasive carcinoma, and renal clear cell carcinoma is distinct from that of their corresponding normal tissues. Moreover, high COMMD10 expression in renal clear cell carcinoma is predictive with improved patient survival (27).