A comprehensive literature search was conducted using PubMed (https://pubmed.ncbi.nlm.nih.gov/) to identify relevant studies on COUP-TFII in CVDs or in CRC. The search covered the literature from January 1900 to January 2025. The inclusion criteria were: i) Original research articles and reviews investigating COUP-TFII expression and function in CVDs or CRC; ii) studies using human tissue samples, cell lines or animal models; iii) original articles and reviews under the key words ‘CVDs’ and ‘CRC’; and iv) articles published in English. The exclusion criteria were: i) Studies lacking specific data on COUP-TFII; and ii) non-English publications. All authors screened the articles, and any discrepancies were resolved through discussion.

As shown in Fig. 1A, COUP-TFII is composed of six regions containing three main domains: An N-terminal domain containing a transcriptional activation function (AF) motif [1–78 amino acids (aa)], a DNA-binding domain (DBD; 79–151 aa) and a C-terminal ligand binding domain (LBD; 177–411 aa), separated by a hinge region (D) (2,3,17).

The N-terminal A/B region containing AF1 motif is required for the recruitment of coactivators or corepressors. DBD, located in the C region, contains two zinc-finger motifs that enable COUP-TFII to bind to specific DNA sequences referred to as direct repeat (DR) motifs composed of the AGGTCA sequence. These sequences are commonly found in the regulatory regions of target genes involved in developmental and metabolic pathways. To regulate a variety of target genes, the DBD of COUP-TFII recognizes and binds to DR elements and palindromic sequences with variable spacing (DR-1, DR-2 and DR-4) within the promoter regions of target genes (2,3,17).

The LBD, located in the E region, facilitates interactions with coactivators such as steroid receptor coactivator-1 (SRC-1) and peroxisome proliferator activated receptor γ coactivator-1α (PGC-1α), and corepressors such as nuclear receptor corepressor (NCoR) and silencing mediator for retinoid or thyroid hormone receptor (SMRT) (2,3,17).

Although COUP-TFII lacks a known endogenous ligand, the LBD modulates transcription through allosteric interactions with coactivators or corepressors. Various classes of molecules can interact with the LBD of COUP-TFII, including endogenous lipids and metabolites (such as retinoic acid derivatives, fatty acids and phospholipids), synthetic small molecules, steroid hormones, peptides and coregulatory proteins (such as NCoR, SMRT and SRC-1). The AF2 motif, located within the LBD, is pivotal for the recruitment of coactivators or corepressors and modulating transcriptional activity. The F region refers to the C-terminal region of the COUP-TFII protein (2,3,17).

COUP-TFII is a ligand-regulated nuclear receptor. Kruse et al (18) demonstrated that COUP-TFII adopts an auto-repressed conformation, as revealed by crystallographic analysis, due to the interaction between the co-factor binding sites and the AF2 motif, preventing co-factor recruitment in the absence of ligands. Ligands, such as retinoic acids, can activate COUP-TFII by releasing it from its auto-repressed conformation (18). The findings of this integrative approach can enhance the translational value of the structural analyses of COUP-TFII in the absence or presence of ligands in drug development. However, to the best of our knowledge, the physiological relevance of ligand regulation remains unclear, with further studies being required to identify endogenous ligands and validate tissue-specific effects.

COUP-TFII can function as either a negative or positive transcriptional regulator via direct binding to DNA response elements (DR sites) or interaction with other transcription factors [such as retinoid × receptor and specificity protein 1 (Sp1)], respectively (3,17). COUP-TFII can inhibit the transcription of target genes via the recruitment of corepressors through the formation of homodimers or heterodimers (Fig. 1B) (2,3). Alternatively, it can also bind to Sp1 sites to activate the transcription of target genes [such as neuropilin 2 and angiopoietin-1 (Ang-1); Fig. 1B] (19,20). The experimental evidence for this mechanism was mainly obtained in in vitro studies and tumor models (19,20). Qin et al (20) used a conditional COUP-TFII knockout strategy in xenograft models to demonstrate that COUP-TFII positively regulated tumor angiogenesis by directly binding to Sp1 binding sites in the promoter regions of angiogenesis-related genes. These findings were supported by robust promoter-reporter assays, chromatin immunoprecipitation (ChIP) and loss-of-function experiments, providing convincing mechanistic evidence. Therefore, in cancer biology contexts, the experimental quality of these studies (19,20) is high. However, beyond oncogenic models, their physiological relevance has yet to be validated. Further studies using cardiovascular- or angiogenesis-specific models are necessary to confirm the functional relevance of COUP-TFII-Sp1 interactions in non-cancer conditions.

The regulatory mechanisms of COUP-TFII expression and activity are not completely understood, because its specific ligand has not yet been fully characterized. The expression and activity of COUP-TFII are tightly regulated by various mechanisms, such as transcriptional and epigenetic regulation, and by interactions with signaling pathways.

COUP-TFII expression has been reported to be modulated by sonic hedgehog (Shh) during developmental processes, because an Shh-responsive element was identified in the COUP-TFII promoter (21). This finding was based on in vitro promoter assays, and although revealing a potential regulatory element, in vivo results were lacking. Thus, the physiological significance of this regulation has yet to be further validated. COUP-TFII expression has also been reported to be regulated by retinoic acid (22,23), estradiol (24) or MAPK pathways (25). Retinoic acid and its derivatives regulate COUP-TFII expression via nuclear receptor-mediated pathways. This regulation is important to maintain tissue homeostasis and differentiation (22,23). However, since the study by Soosaar et al (23) was solely based on in vitro experiments using a combination of cell culture and biochemical assays, their findings may not be generalized. In addition, retinoic acid has been reported to suppress COUP-TFII expression in some contexts (such as the rat glioblastoma C3 and human glioblastoma U373 cell lines), suggesting that the cellular context and specificity of receptor isoforms influence the outcome of retinoic acid signaling (23). COUP-TFII expression is also regulated by other factors, including Oct4 (26), microRNA (miRNA/miR)-302 (26) and Ets-1 (27). COUP-TFII expression has been revealed to be repressed by Oct4, which binds to the COUP-TFII promoter, and by miR-302, which interacts with its 3′-untranslated region (3′-UTR) (26). Oct4, as a key pluripotency factor, interacts with COUP-TFII to regulate its transcriptional activity, particularly in stem cell maintenance and differentiation (26). The findings of Rosa and Brivanlou (26) were based on overexpression and knockdown experiments without addressing potential off-target effects; however, in stem cell models, the results were comprehensive. Furthermore, the suppressive effect of Oct4 on COUP-TFII may not be conserved in non-pluripotent cell types, suggesting that this regulation may be limited by tissue specificity (26). Petit et al (27) revealed that Ets-1, together with SRC-1, could activate COUP-TFII expression in luciferase reporter assays. This study is insightful for providing explainable potential mechanisms. However, its conclusions are derived from in vitro assays, and direct binding of Ets-1 to the endogenous promoter in physiological conditions has yet to be fully demonstrated. COUP-TFII expression is repressed by hypoxia-inducible factor (HIF)-1α in hypoxic endometrial stromal cells (28) and by the artery-specific Δ-like canonical Notch ligand 4 - Notch-hairy/enhancer of split-related with YRPW motif protein 2 (Hey2) signaling axis in endothelial progenitor cells under hypoxic conditions (29). Both studies (28,29) emphasized the importance of hypoxic signaling; however, since the results are confined to specific cell types, they do not address whether similar regulation occurs in other cell lineages.

miRNAs are known to be important post-transcriptional regulators in cancer (30). In particular, Yun and Park (11) reviewed regulation of COUP-TFII expression by miRNAs. For example, miRNA-27b downregulates COUP-TFII expression through interaction with its 3′-UTR, leading to the inhibition of proliferation and invasion of gastric cancer cells in vitro, and metastasis of gastric cancer cells to the liver in vivo (31). A study by Feng et al (31) demonstrated both in vitro and in vivo effects, which reinforces its conclusions. However, the mechanistic association between COUP-TFII suppression and phenotypic outcomes was not directly validated by rescue experiments, leaving room for alternative explanations. Additionally, miR-302, miR-302a, miR-382, miR-101, miR-27a and miR-194 have been reported to downregulate COUP-TFII expression, and to have diverse functions in different cell types, such as embryonic stem cells, mesenchymal C3H10T1/2 cells, colorectal cancer cells and prostate cancer cells (26,32–37). These studies used luciferase reporter assays, reverse transcription-quantitative PCR and western blot analyses to demonstrate miRNA-mediated repression of COUP-TFII. However, the studies have several limitations. For example, Rosa and Brivanlou (26) based their findings on embryonic stem cells, limiting their applicability to cancer. For miR-382 and miR-101 (34–36), COUP-TFII downregulation was observed, but indirect effects could not be excluded. In the case of miR-27a (36), opposing roles in different tissues suggest context dependence. The study by Jeong et al (37) demonstrated that miR-194 functions as a key regulator of COUP-TFII in mesenchymal stem cells, directing their fate toward differentiation into osteoblasts and adipocytes.

Overall, although evidence supports the miRNA-based regulation of COUP-TFII, context specificity, functional redundancy and cell type-dependent expression complicate the identification of consistent regulatory mechanisms.

Activation of the MAPK pathway has been reported to increase COUP-TFII expression in certain cellular contexts. For example, in breast cancer cell lines with elevated MAPK activity, COUP-TFII levels are increased (25), suggesting that this pathway can upregulate COUP-TFII as part of a broader cellular response to growth signals. However, the precise relationship between MAPK signaling and COUP-TFII expression is complex, and appears to vary depending on the specific cell type and environmental context. This study examined the association between MAPK signaling and COUP-TFII upregulation in breast cancer models using pharmacological inhibitors, suggesting an association between pathway activation and COUP-TFII expression (25). However, it lacks evidence regarding direct transcriptional regulation by MAPK effectors, such as ERK, ETS like-1 protein or c-fos. The study also used a limited number of cell lines, and failed to investigate potential pathway interactions, such as crosstalk with PI3K/AKT or hormonal signaling.

Notch signaling serves an antagonistic role in regulating COUP-TFII expression (10,29). In endothelial cells (ECs), activation of Notch signaling leads to a reduction in COUP-TFII levels, which in turn promotes arterial differentiation (10,42). Conversely, COUP-TFII can inhibit Notch signaling to maintain venous identity, thereby influencing cell fate decisions during vascular development (10,42). This reciprocal regulation emphasizes the role of COUP-TFII in establishing and preserving vascular heterogeneity. Taken together, these findings are supported by studies (10,42) using genetic mouse models, lineage tracing and molecular assays that demonstrate a causal association between Notch activation and COUP-TFII downregulation in ECs during vascular development. However, the majority of the studies (10,42) focused on embryonic or early postnatal stages, leaving its role in adult or pathological conditions unclear. It is also uncertain whether this regulatory axis applies to other vascular beds, such as lymphatic or tumor endothelium. While mutual antagonism between COUP-TFII and Notch in development processes has been established, its dynamics in disease contexts require further investigation across diverse tissues.

COUP-TFII expression has been reported to be upregulated by the Wnt/β-catenin pathway (43). ChIP assays have demonstrated that β-catenin/T-cell factor 7-like 2 or transcription factor 7-like 2 (TCF7L2) complexes bind directly to the COUP-TFII promoter, leading to increased transcription. This interaction is notable in the context of cell differentiation. For example, activation of Wnt signaling, leading to the upregulation of COUP-TFII via β-catenin/TCF7L2 complexes, results in the suppression of adipocyte differentiation by inhibiting the expression of the adipogenic transcription factor peroxisome proliferator-activated receptor (PPAR)γ (43). Okamura et al (43) demonstrated that β-catenin/TCF7L2 directly bound to the COUP-TFII promoter in ChIP and reporter assays in preadipocyte models, and confirmed Wnt-mediated regulation through gain- and loss-of-function approaches. However, the focus of the study on adipocytes limited the generalizability to other cell types. It also remains undefined whether upregulation of COUP-TFII is a primary Wnt response, or a downstream effect. Broader in vivo and multi-lineage studies are needed to fully define the mechanisms by which Wnt signaling modulates COUP-TFII expression.

COUP-TFII is predominantly expressed in venous ECs, the atria, coronary arteries, the aorta (44) and vascular smooth muscle (8). COUP-TFII is important for proper vascular development (7). An in vivo study revealed that genetic ablation of COUP-TFII induces the ectopic expression of arterial markers in venous ECs, whereas forced expression of COUP-TFII in arterial cells suppresses arterial gene expression, underscoring its role as a molecular switch in vascular differentiation (10). Mechanistically, COUP-TFII binds to cis-regulatory elements at key loci, such as HEY2 and FOXC1 which are required for arterial differentiation. By binding to their regulatory regions, COUP-TFII inhibits the activation of the arterial differentiation program (42). A study by Sissaoui et al (45) demonstrated that in venous ECs, COUP-TFII recruited histone deacetylases (HDACs) to actively repress the expression of HEY2, a key mediator of arterial identity. Furthermore, COUP-TFII interacted with ETS-related gene (ERG) to induce the expression of several vein-specific genes, such as family with sequence similarity 174 member B, a disintergrin and metalloprotease with thrombospondin motifs 18 and LIM homeobox 6 (45).

The working model proposed by Sissaoui et al (45) suggests that a regulatory element (the −161K enhancer) acts as a bimodal switch depending on the cellular context: In venous ECs, COUP-TFII occupies this enhancer to block ERG-mediated activation of HEY2, whereas in arterial ECs lacking COUP-TFII, ERG binds to the −161K enhancer and promotes arterial gene expression. In the study by Sissaoui et al (45), CRISPR-CRISPR-associated protein 9 enhancer deletion, ChIP-sequencing and reporter assays were effectively used to define the COUP-TFII-HDAC-ERG axis and demonstrate the role of COUP-TFII as a repressor of arterial identity in venous ECs. However, the focus on embryonic tissues and human umbilical vein ECs limits the relevance to adult vasculature and pathological angiogenesis. In pathological settings such as tumors, COUP-TFII expression can persist in vessels with arterial features, suggesting that its regulatory role may be more flexible than previously suggested (20). Broader, context-specific studies are needed to clarify its function in vascular remodeling.

Cui et al (46) revealed the role and molecular mechanism of COUP-TFII in adult vascular endothelium, demonstrating that knockdown of COUP-TFII in adult vascular ECs upregulated the expression levels of inflammatory genes [such as C-X-C motif chemokine ligand (CXCL)10, CXCL11 and C-C motif chemokine ligand (CCL)5], while downregulating the expression levels of antithrombotic genes [such as tissue factor pathway inhibitor 2 (TFPI2)]. This dysregulation could trigger endothelial-to-mesenchymal transition (EndMT). Furthermore, the expression levels of arterial markers (such as ephrin-B2 and hes family bHLH transcription factor 1/4), expression of genes involved in angiogenesis [such as endothelial PAS domain protein 1/HIF-2α, ephrin-A1, tyrosine kinase with immunoglobulin like and EGF like domains-2 (Tie-2) and ephrin-A4] and the osteogenic potential leading to calcium deposition of adult ECs were suppressed by COUP-TFII overexpression. Cui et al (46) demonstrated that the actions of COUP-TFII in adult ECs may be mediated by its negative regulation of bone morphogenic protein 4 (BMP4) through direct binding to the BMP4 promoter. These results suggest that COUP-TFII serves a key role in maintaining the venous identity in adult ECs, as well as during development (46). This study focused on adult ECs, a less explored context for COUP-TFII. Cui et al (46) used in vitro knockdown/overexpression and ChIP assays to reveal that COUP-TFII suppressed pro-inflammatory, angiogenic and osteogenic gene programs, reinforcing their conclusions. However, reliance on cultured ECs limits in vivo relevance, while other pathways regulating BMP4 were not fully excluded. Their findings suggest anti-inflammatory and anti-osteogenic roles of COUP-TFII in adult ECs, which are inconsistent with reports of its pro-angiogenic and immunosuppressive effects in tumor models (17,20). These discrepancies underscore context-dependent functions of COUP-TFII and emphasize the need for further investigations in normal vs. diseased adult vasculature.

Angiogenesis, the formation of new blood vessels, relies on coordinated interactions among shear stress, vascular growth factors such as VEGF and Ang-1 (a ligand for Tie-2), intracellular signaling pathways (such as Notch) and intercellular contacts (47–54).

Knockdown experiments in mouse aortic vascular smooth muscle cells and C3H10T1/2 fibroblasts have revealed that COUP-TFII positively regulates Ang-1 expression levels (20). This regulation occurs through the direct binding of COUP-TFII, in cooperation with Sp1, to the Ang-1 promoter. The upregulation of Ang-1 by COUP-TFII suggests a pro-angiogenic role, promoting vessel stability and maturation (20). However, this study (20) was limited by its dependence on in vitro fibroblast and smooth muscle cell models, which may not reflect the in vivo angiogenic environment. Although ChIP assays verified COUP-TFII binding to the Ang-1 promoter, its functional relevance in ECs in vivo remains unvalidated. Furthermore, the role of COUP-TFII in angiogenesis appears to be context-dependent, while it can promote Ang-1 expression, another study has revealed that it may suppress VEGF receptor expression and inhibit sprouting, particularly in tumors (55). These conflicting findings suggest that COUP-TFII may balance vascular stabilization and angiogenic modulation in a tissue- and context-specific manner.

Dysregulation of COUP-TFII can lead to pathological angiogenesis, contributing to various vascular diseases, such as atherosclerosis and pulmonary arterial hypertension (PAH) (56). For instance, in multiple types of human ECs (e.g., lung microvascular, coronary artery and pulmonary artery ECs), knockdown of COUP-TFII activates the AKT and STAT signaling pathways. This activation is accompanied by an increase in Dickkopf-related protein 1 expression, resulting in a pro-inflammatory, proliferative, hypermigratory and apoptosis-resistant phenotype. These changes are further characterized by the induction of EndMT, increased oxidative stress, enhanced lactate production and the upregulation of glycolytic genes, such as hexokinase 2, lactate dehydrogenase A and 6-phosphofructo-2-kinase/fructose-2,6-bisphophatase 3 (PFKFB3) (56). The strengths of this study include the use of multiple types of ECs, and the integration of molecular, metabolic and phenotypic analyses (56). However, key limitations include the reliance on in vitro knockdown models, which may not fully reflect the complexity of the in vivo vascular environment.

Suppression of COUP-TFII has been associated with the induction of glycolytic and lipogenic pathways (57,58). Elevated PFKFB3 levels, in particular, destabilize atherosclerotic plaques and contribute to the progression of atherosclerosis (59). Similarly, enhanced endothelial glycolysis and proliferation, driven by COUP-TFII suppression, may underlie the pathogenesis of PAH (57,60). These studies are notable for their mechanistic data associating metabolic shifts with vascular dysfunction and their use of relevant EC models (57,60). However, limitations include a lack of in vivo causal data, and uncertainty regarding whether the metabolic changes are a primary driver, or a secondary effect, of the diseases. Furthermore, other studies suggest that COUP-TFII loss may induce protective metabolic adaptations in other contexts, indicating potential tissue- or disease-specific variability that warrants further investigation (3,5).

Several studies have demonstrated that COUP-TFII acts as a tumor suppressor in CRC (80–83). A retrospective study using tissue microarray assays have indicated that high COUP-TFII expression is associated with improved survival rates and reduced lymph node metastasis in patients with CRC; however, the initial study was limited by small sample sizes and short follow-up periods (80). These findings have subsequently been confirmed in larger cohorts with extended follow-up durations (81), supporting the hypothesis that COUP-TFII exerts tumor-suppressive effects in CRC.

Functional studies in human CRC cells have provided mechanistic insights. In SNU-C4 cells, COUP-TFII overexpression suppressed proliferation and invasion by upregulating the tumor suppressors p53 and PTEN, and by inhibiting Akt activity, respectively (82,83). Conversely, COUP-TFII knockdown in HT-29 CRC cells enhanced cell proliferation and invasive capabilities through the activation of the Akt pathway, leading to glycogen synthase kinase-3 β inactivation, β-catenin stabilization, and the upregulation of MMP7 and FOXC1 (83); however, the use of only two CRC cell lines (SNU-C4 and HT-29) limits the generalizability. These results underscore the function of COUP-TFII as a negative regulator of tumor aggressiveness in CRC. However, additional in vivo validation studies are necessary to confirm these findings and fully elucidate the mechanism by which COUP-TFII modulates CRC progression.

By contrast, a growing body of evidence indicates a tumor-promoting role of COUP-TFII under certain conditions. For example, patients with CRC with high COUP-TFII expression have an increased risk of metastasis and reduced overall survival, compared with patients with CRC with low COUP-TFII expression (84,85). Mechanistically, COUP-TFII directly binds to the promoter region of the Snail1 gene, a master regulator of EMT, leading to the suppression of E-cadherin and increased immunosuppressive signaling (84,86–88). Additionally, miR-21, an oncomiR highly expressed in various types of cancer (89), increases COUP-TFII expression, which in turn promotes TGF-β-induced EMT by inhibiting Smad7 (90). COUP-TFII can also regulate the expression of miR-34a (91), a well-known tumor suppressor miRNA that inhibits tumor cell migration and promotes chemosensitivity (92–95). Notably, COUP-TFII-regulated miR-21 inhibits PTEN and elevates the levels of prostaglandin E₂, a pro-inflammatory and pro-tumorigenic mediator, by suppressing 15-hydroxyprostaglandin dehydrogenase, further contributing to tumor progression and inflammation (3,90). Although these findings are supported by cell and animal models, limitations remain, including reliance on overexpression systems, and unclear relevance across different types of cancer. A conflicting report of the anti-inflammatory roles of COUP-TFII in other tissues suggests context-dependent effects (96), emphasizing the need for further validation in human tumors and diverse inflammatory settings.

Despite the controversial roles of COUP-TFII in CRC, growing evidence (3,5,20,46,69,82,89,90) has associated chronic inflammation, oxidative stress, angiogenesis and metabolic dysregulation with both CVDs and CRC, with COUP-TFII serving as a common molecular regulator. Fig. 2 illustrates the molecular mechanisms by which COUP-TFII functions as a common regulator in both CVDs and CRC.

Based on published reports (46,108) and the aforementioned descriptions, chronic inflammation is involved in both CVDs and CRC (Fig. 2). As previously mentioned (46), COUP-TFII is key to maintain endothelial homeostasis. In adult vascular ECs, it represses the expression of pro-inflammatory cytokines (such as CXCL10, CXCL11 and CCL5), while supporting the expression of anti-thrombotic genes, such as TFPI2. Loss or reduced expression of COUP-TFII can lead to an inflammatory endothelial state, triggering EndMT, which contributes to atherosclerosis and other vascular pathologies (46). In the tumor microenvironment of CRC, chronic inflammation is a known driver of cancer progression (108). COUP-TFII appears to serve a dual role, depending on the cellular context. In some CRC cells, overexpression of COUP-TFII promotes tumor-suppressive signaling by upregulating p53 and PTEN while inhibiting Akt (82), which can help reduce inflammation. However, in other contexts, increased COUP-TFII expression, especially when upregulated by miRNAs such as miR-21, can promote EMT through activation of inflammatory pathways, thereby enhancing tumor invasiveness (3,89,90).

Oxidative stress serves an important role in both CVDs and CRC (Fig. 2). In the heart and vasculature, COUP-TFII is involved in the regulation of mitochondrial function. Upregulation in cardiac tissues has been associated with defects in the ETC, and a reduction in the expression of mitochondrial quality control genes (such as Mfn1, Mfn2, Opa1 and Pink1). This leads to the accumulation of damaged mitochondria and impaired ROS scavenging, culminating in elevated oxidative stress, a key factor in heart failure and vascular disease progression (69). While the study by Wu et al (69) is pivotal in terms of mechanistic exploration using transgenic mouse models of DCM, some limitations should be addressed. First, the cardiac-specific effects of COUP-TFII may not be directly generalizable to other tissues, including the colon. Second, although the mitochondrial dysfunction and oxidative stress were associated with COUP-TFII levels, direct causality and dose-response relationships were not fully established, particularly with respect to downstream disease phenotypes. In CRC, oxidative stress within the tumor microenvironment can promote genetic instability and tumor progression (109). However, lack of direct evidence associating COUP-TFII with ROS regulation in CRC leaves the proposed relationship speculative. To the best of our knowledge, the majority of the existing data, including the aforementioned study by Yang et al (109), focus on general mechanisms of ROS in cancer, and do not specifically implicate COUP-TFII. Therefore, while it is plausible that regulation of metabolic and mitochondrial pathways by COUP-TFII could indirectly influence ROS levels in CRC, this hypothesis remains unvalidated in CRC-specific in vivo models. Further research using CRC-specific conditional knockout or overexpression models is essential to clarify whether COUP-TFII modulates oxidative stress in the colon epithelium or tumor microenvironment and whether this mechanism contributes causally to colorectal tumorigenesis.

COUP-TFII regulates angiogenesis, affecting the progression of both CVDs and CRC (Fig. 2). COUP-TFII positively regulates angiogenic factors such as Ang-1 by binding to its promoter (often in cooperation with Sp1), which supports vessel stability and maturation (46). This function is key for normal vascular repair and to prevent pathological calcification (46). In CRC, COUP-TFII modulates the balance between pro- and anti-angiogenic signals. By influencing the expression of factors that control angiogenesis, COUP-TFII can impact tumor vascularization (17,20). Depending on the cellular context, this modulation may either suppress or promote tumor progression.

COUP-TFII also regulates energy metabolism, influencing both cardiac function and cancer cell proliferation (Fig. 2). COUP-TFII regulates various genes such as GLUTt4, PPARα, fatty acid binding protein 3 and carnitine palmitoyltransferase 1 involved in both fatty acid and glucose metabolism (3,5). Upregulation of COUP-TFII in cardiac tissues has been associated with the downregulation of key metabolic regulators, such as PGC-1α and Sod2, leading to mitochondrial dysfunction, impaired energy production and ultimately heart failure (69). In CRC, COUP-TFII can influence metabolic pathways through its effects on the Akt signaling cascade and by altering the expression of enzymes involved in glycolysis (5). This metabolic dysregulation provides the energetic and biosynthetic requirements for rapid tumor cell proliferation, thereby contributing to cancer progression.