Colorectal cancer (CRC) ranks as the third most common cancer and the second leading cause of cancer-related mortality worldwide (52, 53). Despite its high global death rate, CRC is preventable and curable with timely intervention (54, 55). Increasing evidence indicates that circFOXP1 is significantly upregulated in colon cancer cells and tissues compared to normal tissues (51). These findings suggest that circFOXP1 may play a crucial role in the initiation and progression of colon cancer. In vivo studies have demonstrated that circFOXP1 promotes tumor growth, metastasis, invasion, and reduces sensitivity to chemotherapy. Furthermore, the expression level of circFOXP1 correlates with tumor stage and overall survival, with high circFOXP1 expression associated with advanced tumor stages and poorer survival outcomes (16). While research on circFOXP1 in colon cancer is substantial, studies in rectal cancer are limited, necessitating further investigation to clarify its role in rectal cancer. Nevertheless, circFOXP1 remains a promising candidate for diagnostic, therapeutic, and prognostic applications in colorectal cancer.

Lung cancer is primarily classified into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) (56). Among NSCLC, lung adenocarcinoma (LUAD) is a prominent subtype (57). The role of circFOXP1 in lung adenocarcinoma exhibits a dual nature. On one hand, some studies have reported that circFOXP1 is downregulated in LUAD tissues, where it can inhibit tumor cell growth and accelerate apoptosis both in vivo and in vitro (38). On the other hand, elevated levels of circFOXP1 have been observed in lung adenocarcinoma cells and tissues compared to normal tissues, with high circFOXP1 expression correlating with poor patient prognosis (39, 40). Additionally, in some bioinformatics studies, circFOXP1 has been identified as a tumor suppressor molecule in lung cancer (58, 59). This dichotomy suggests that circFOXP1 may exert different biological functions depending on the molecular environment or experimental conditions. This highlights the need for more in-depth research to elucidate the specific mechanisms of circFOXP1 in various contexts and its potential as a therapeutic target. Investigating these contrasting findings could enhance our understanding of circFOXP1’s multifaceted role in lung cancer and inform the development of personalized treatment strategies. However, research on circFOXP1 in the highly malignant SCLC remains limited.

Gastric cancer (GC) ranks as the fifth most common cancer globally and the third leading cause of cancer-related mortality (60, 61). The high mortality rate is largely due to the lack of early clinical symptoms and diagnostic tools, resulting in most GC patients being diagnosed at an advanced stage (62). Consequently, the prognosis for GC patients is generally poor (63). Studies have reported that elevated circFOXP1 expression in gastric cancer tissues and cells is closely associated with unfavorable clinical outcomes, while patients with lower circFOXP1 levels tend to have better prognoses. This is often reflected in clinical features such as lymphatic metastasis, TNM stage, and tumor size. Moreover, patients with high circFOXP1 levels exhibit significantly higher overall mortality compared to those with lower levels. In vivo experiments further demonstrate that knocking down circFOXP1 inhibits GC tumor growth (43). Collectively, these findings underscore the critical role of circFOXP1 in GC progression and highlight its potential clinical value as a prognostic marker and therapeutic target in gastric cancer.

Liver cancer is the sixth most common cancer globally and the third leading cause of cancer-related deaths (52, 64). Hepatocellular carcinoma (HCC) is the most prevalent form of primary liver cancer (65). Extensive research has demonstrated a close association between circRNA expression and HCC (66, 67). In studies focusing on hepatocellular carcinoma with Catenin beta 1 (CTNNB1) mutations, circFOXP1 expression was found to be dysregulated in liver cancer tissues (68). Additionally, research by Wang et al. (47) revealed that high circFOXP1 expression is significantly correlated with larger tumor size, microvascular invasion, advanced TNM stage, and poor prognosis. In serological studies, the diagnostic ROC curve of circFOXP1 suggests its potential value as a biomarker in HCC. In vitro experiments indicate that knocking down circFOXP1 inhibits HCC cell proliferation and invasion while promoting apoptosis; in vivo, circFOXP1 exacerbates HCC tumor formation and increases Ki67 expression. These findings suggest that circFOXP1 accelerates HCC progression. Intrahepatic cholangiocarcinoma (ICC), though relatively rare, is an extremely aggressive type of tumor that responds poorly to chemotherapy and immunotherapy (69). ICC accounts for approximately 10%-15% of all liver cancer cases (70). Interestingly, research on circFOXP1 in ICC contrasts with findings in HCC. Overexpression of circFOXP1 in ICC reduces tumor size and lowers Ki67 expression, while knockdown of circFOXP1 produces the opposite effect. High circFOXP1 expression is associated with longer survival times and lower recurrence rates in ICC patients (46). These results indicate that circFOXP1 plays an antitumor role in ICC and may serve as a favorable prognostic marker. In summary, circFOXP1 exhibits distinct mechanisms of action in HCC and ICC. This differential role suggests that circFOXP1 may function through different molecular pathways in various types of liver cancer, necessitating divergent therapeutic strategies for HCC and ICC. These findings provide valuable insights for further exploration of the molecular mechanisms of circFOXP1 in different liver cancers.

Gallbladder cancer (GBC) is a relatively rare but highly lethal malignancy with a poor prognosis (71, 72). Radical surgery is the only curative treatment for GBC, but the high risk associated with late-stage surgery limits its applicability (73). Therefore, novel immunotherapies for advanced GBC and early diagnostic methods are of paramount importance. Research has shown that high circFOXP1 expression is closely associated with lymph node metastasis and advanced TNM stage in GBC patients. The expression levels of circFOXP1 in GBC tissues are significantly higher than in normal, non-tumorous gallbladder tissues. Downregulation of circFOXP1 impairs GBC cell proliferation, induces G1-S phase arrest, and increases apoptosis rates, with concomitant reductions in the expression of PCNA, MMP9, and AKT. Conversely, upregulation of circFOXP1 enhances GBC cell proliferation. Moreover, in animal model experiments, circFOXP1 knockdown inhibited tumor growth, while its overexpression had the opposite effect (41). Thus, elevated circFOXP1 levels significantly promote GBC cell proliferation, invasion, and distant metastasis. These findings suggest that circFOXP1 could serve as a novel diagnostic biomarker and potential therapeutic target for GBC.

Osteosarcoma is one of the most common primary bone tumors, with a 5-year survival rate of less than 20% after metastasis (74). The mechanisms of neovascularization include angiogenesis, sprouting, intussusception, vessel co-option, vasculogenic mimicry, and lymphangiogenesis (75). Angiogenesis provides cancer cells with oxygen and nutrients, playing a crucial role in cancer cell survival and metastasis (76). Recent studies have indicated that circFOXP1 is highly expressed in osteosarcoma and is negatively correlated with patient survival rates. Functional mouse models have demonstrated that low expression of circFOXP1 reduces microvascular density in osteosarcoma tumors, leading to a decrease in tube formation ability (44). These findings suggest that circFOXP1 promotes neovascularization in osteosarcoma and plays a critical role in angiogenesis. Although progress has been made in osteosarcoma treatment, patient outcomes remain poor. Therefore, exploring new therapeutic strategies targeting neovascularization in osteosarcoma is of significant importance.

Ovarian cancer is the eighth most common cancer in women and is known for its high malignancy (77, 78). CircRNAs play a major role in the proliferation, migration, and progression of ovarian cancer cells (79). Reports have shown that the expression of exosomal circFOXP1 is significantly higher in patients with epithelial ovarian cancer (EOC) who are resistant to cisplatin (DDP) compared to DDP-sensitive patients. Additionally, the expression of exosomal circFOXP1 in patient serum is significantly correlated with FIGO stage, primary tumor size, lymph node metastasis, distant metastasis, residual tumor diameter, and clinical response. Overexpression of circFOXP1 is associated with poor prognosis in EOC patients. Moreover, knocking down circFOXP1 enhances the sensitivity of EOC cells to DDP and reduces the expression of the tumor growth marker Ki67 (45). Renal cell carcinoma (RCC) is the second most common cancer of the urinary system (80). Studies have found that downregulating circFOXP1 can inhibit RCC proliferation, migration, invasion, and reduce the Warburg effect (48). In cutaneous squamous cell carcinoma (cSCC), circFOXP1 expression is upregulated compared to non-cancerous skin tissues. Silencing circFOXP1 has been shown to inhibit the proliferation of cSCC cells (13). Therefore, circFOXP1 may serve as a potential therapeutic target in these cancers. Targeting circFOXP1 could help suppress tumor progression and overcome chemotherapy resistance.

Osteonecrosis of the femoral head (ONFH) is a common and challenging orthopedic condition, often leading to hip pain and functional impairment. It has a high disability rate, imposing a heavy burden on patients, their families, and society (81). Studies have shown that circFOXP1 is upregulated during the osteogenic induction of bone marrow mesenchymal stem cells (BMSCs). Knocking down circFOXP1 can inhibit the proliferation and osteogenic differentiation of BMSCs, with a noted decrease in the expression levels of RUNX2, OPN, and OCN (14). CircFOXP1 is thus considered a key activator in the treatment of ONFH.

Acute ischemic stroke (AIS) is a leading cause of death worldwide, with high rates of disability and mortality (82, 83). Elevated circFOXP1 expression is considered a protective factor for AIS prognosis, as indicated by both univariate and multivariate analyses. ROC curve analysis has demonstrated the potential of circFOXP1 as a predictor of poor outcomes. Studies have shown that circFOXP1 expression is significantly reduced in the peripheral blood of AIS patients and is associated with the severity and prognosis of AIS. Specifically, circFOXP1 levels are inversely correlated with infarct size and the levels of fibrinogen, D-dimer, α-hydroxybutyrate dehydrogenase, and lactate dehydrogenase in the blood. This trend is also observed in animal models. Knockdown of circFOXP1 induces the expression of pro-apoptotic proteins (Bax and Caspase-3) and suppresses the expression of the anti-apoptotic protein Bcl2 in human glioblastoma cells. Conversely, overexpression of circFOXP1 inhibits Bax and Caspase-3 expression while inducing Bcl2 expression (49). CircFOXP1 holds potential as a biomarker for assessing prognosis in AIS patients and may serve as a novel therapeutic target for treating AIS.

Pulmonary fibrosis (PF) gradually affects the lung parenchyma, leading to impaired gas exchange, difficulty breathing, decreased quality of life (QoL), and ultimately resulting in respiratory failure and death (84). In studies investigating the effects of human umbilical cord mesenchymal stem cells (hucMSCs) on PF, it has been found that the therapeutic efficacy of hucMSCs in inhibiting PF is dependent on the downregulation of circFOXP1. In animal experiments, mice treated with hucMSCs exhibited significant improvements, including thinner alveolar walls, better-preserved alveolar structure, reduced alveolar inflammation, and decreased collagen deposition. Furthermore, fibrosis-related proteins such as vimentin, α-SMA, collagen I, collagen III, and the differentiation marker S100A4 were significantly reduced in the hucMSCs-treated group (17). These findings suggest that circFOXP1 plays a promotive role in the development of PF, and that hucMSCs may offer a promising therapeutic approach by downregulating circFOXP1.

Recurrent pregnancy loss (RPL) is defined as the failure of two or more clinical pregnancies and is a common issue among women of reproductive age (85, 86). Clinical investigations have revealed that the level of miR-143-3p is significantly upregulated in the placental tissues of RPL patients, while circFOXP1 acts as a ceRNA for miR-143-3p in trophoblast cells. It has been observed that the expression of circFOXP1 is downregulated in these patients. Overexpression of circFOXP1 has been shown to enhance the viability of HTR8/SVneo cells, reduce apoptosis, and promote cell migration and invasion, thereby improving trophoblast cell function (19). The downregulation of circFOXP1 may lead to trophoblast dysfunction, thereby increasing the risk of RPL. Therefore, circFOXP1 could be a potential therapeutic target for RPL.

Keloids are pathological scars that cause significant functional and cosmetic burdens (87). A study found that the levels of circFOXP1 were higher in keloid tissues compared to normal skin tissues. Overexpression of circFOXP1 significantly promoted the proliferation and migration of human skin fibroblasts (HSFs) while inhibiting apoptosis. This upregulation of circFOXP1 led to enhanced keloid growth in vivo, along with increased deposition of extracellular matrix (ECM) proteins such as α-SMA, collagen I, and collagen III (50). Thus, circFOXP1 plays a promotive role in keloid formation by accelerating fibroblast proliferation and migration, as well as increasing ECM protein deposition, thereby driving the development of keloids.

Atherosclerosis is a chronic inflammatory vascular disease driven by both traditional and non-traditional risk factors (88). Research has shown that circFOXP1 is significantly upregulated in atherosclerosis (AS) mouse models and AS cell models. In addition, in apolipoprotein E-deficient mice induced by a high-fat diet (HFD), circFOXP1 was found to promote the upregulation of pro-inflammatory cytokines such as interleukin IL-6, TNF-α, and IL-1β, further exacerbating endothelial cell injury (20). CircFOXP1 plays a promotive role in the development of atherosclerosis, with its upregulation associated with increased inflammatory factors, thereby worsening endothelial cell damage. This suggests that circFOXP1 may be an important regulator of inflammation in atherosclerosis and could serve as a potential therapeutic target.

Osteoporosis (OP) is a skeletal disorder characterized by compromised bone structure and strength, leading to an increased risk of fragility fractures (89). CircFOXP1 has been found to be significantly downregulated in the bone tissue of OP patients. Furthermore, circFOXP1 promotes new bone formation in mice, with more collagen fiber bundles and an increased presence of brown-staining particles, indicating its role in regulating osteogenesis in human adipose-derived mesenchymal stem cells (hASCs) (18). However, the clinical trial involving the isolation of hASCs from patients, seeding them onto composite grafts, and reimplanting them into fracture sites (https://clinicaltrials.gov/study/NCT01532076) has yet to be completed. Therefore, further preclinical and clinical studies are necessary to determine the therapeutic potential of circFOXP1 in treating osteoporosis.

CircFOXP1 is recognized as a specific molecular marker of undifferentiated mesenchymal stem cells (MSCs). Knockdown of circFOXP1 has been shown to reduce MSC growth, with a concomitant decrease in the expression levels of MSC markers such as CD164, PDPN, CD146, and GLI1. Additionally, the abundance of CD90+/CD146+ and CD73+/CD105+ double-positive populations diminishes, leading to impaired MSC differentiation capabilities (90). Therefore, circFOXP1 plays a crucial role in maintaining the undifferentiated state, marker expression, and differentiation potential of MSCs. CircFOXP1 may be a key molecule in regulating the biological functions of MSCs.

The competitive endogenous RNA (ceRNA) regulatory network represents a pivotal mechanism through which circFOXP1 exerts its influence in disease pathogenesis. By functioning as a ceRNA, circFOXP1 can act as a miRNA sponge, thereby modulating the expression of downstream messenger RNAs (mRNAs) and influencing disease progression (as shown in Figure 3 and Figure 2E). Theoretically, any RNA possessing miRNA response elements (MREs) has the potential to bind miRNAs and thus perform the role of a ceRNA (92). Given their inherent MREs, circRNAs naturally possess the capability to sequester miRNAs (93). Notably, circFOXP1 has been identified to sponge miR-127-5p, thereby regulating ADCY7 and CDKN2AIP, which promotes the progression and angiogenesis of epithelial ovarian cancer and osteosarcoma, respectively (13, 44). Similarly, a series of experimental analyses in colorectal cancer cell lines have confirmed the existence of the circFOXP1/miR-338-3p/ETS1 axis (51). Interestingly, circFOXP1 exhibits a dual role in lung cancer, acting as both an oncogenic factor and a tumor suppressor. On one hand, circFOXP1 can sequester miR-490-3p, miR-520a-5p, miR-185-5p, miR-370-3p, or miR-18a-5p, preventing the degradation of their downstream target transcripts, thereby enhancing the expression of SYT1, SLC7A11, and WNT1, which in turn promotes tumor cell proliferation, migration, and invasion (39, 40, 42, 91). On the other hand, the circFOXP1/miR-574-5p/RND3 axis has been found to inhibit cell proliferation and promote apoptosis (38). Moreover, circFOXP1 can regulate various axes, including miR-338-3p/SOX4 (43), miR-150-3p/FMNL3 (45), miR-423-5p/U2AF2 (48), miR–143–3p/S100A11 (19), miR-185-5p/BCL-2 (20), and miR-33a-5p/FOXP1 (18), thereby playing a critical role in disease initiation, progression, and response to therapy by modulating processes such as cell proliferation, migration, invasion, apoptosis, drug resistance, epithelial-mesenchymal transition (EMT), and the Warburg effect.In summary, circFOXP1, functioning as a ceRNA, intricately modulates multiple biological properties of human diseases through its interactions with miRNAs. This mechanism is not only fundamental to the biological behavior of tumor cells but also significantly impacts disease progression and prognosis.

Beyond its role as a miRNA sponge, circRNA can also function as a sponge for RNA-binding proteins (RBPs). For instance, Zhang et al. identified RACK1, an RNA-binding protein, as a potential target of circFoxp1 through RNA pull-down assays. RACK1 is known to inhibit collagen synthesis in keloid fibroblasts by suppressing the TGF-β1/Smad signaling pathway (94). CircFoxp1 can downregulate RACK1 expression, potentially serving as a modulator of cell proliferation and apoptosis throughout the keloid formation process (50). In studies on pulmonary fibrosis, the inhibitory effects of hucMSC treatment on lung fibrosis were found to be dependent on the downregulation of circFOXP1. hucMSC treatment promotes the circFOXP1-mediated autophagy process by blocking the translocation of human antigen R (HuR) and facilitating its degradation, leading to a significant reduction in autophagy-negative regulators EZH2, STAT1, and FOXK1, thereby ameliorating lung mononuclear fibrosis (17). Additionally, under hypoxic conditions, the expression of circFOXP1 in the brain is reduced. This reduction exacerbates brain injury following ischemia by binding to and enhancing the ubiquitination of STAT3, accelerating the degradation of signal transducer and activator of transcription 3 (STAT3) protein, ultimately triggering apoptotic signaling pathways (49). Furthermore, Wang et al. discovered that the RNA-binding protein PTBP1 interacts with circFOXP1 in GBC cells. The exogenous expression of circFOXP1 enhances PTBP1 expression by increasing its translocation from the nucleus to the cytoplasm, while knockdown of circFOXP1 results in the retention of PTBP1 within the nucleus (41). Through its interactions with various RNA-binding proteins, circFOXP1 plays a regulatory role in numerous diseases (as shown in Figure 2C ). These interactions not only affect key biological processes such as cell proliferation, apoptosis, and autophagy but also have significant regulatory functions in specific diseases like keloid, pulmonary fibrosis, cerebral ischemia, and gallbladder cancer, suggesting that circFOXP1 could be an important regulatory factor in these conditions.

Epigenetics refers to changes in gene expression that are not attributable to alterations in the DNA sequence itself but rather to chemical modifications of DNA and associated proteins. These modifications can profoundly influence gene expression, cellular differentiation, tissue development, and susceptibility to diseases (95, 96). Among the various epigenetic mechanisms, DNA methylation is particularly notable for its extensive role in gene expression regulation and developmental processes (97, 98). The epigenetic mechanisms associated with circFoxp1 are also integral to its interactions with RBPs (Figure 2A). Research in colorectal cancer has revealed that overexpression of circFoxp1 significantly increases the methylation level of the Foxp1 promoter, while knockout of circFoxp1 notably reduces this methylation. CircFoxp1 forms an RNA-protein complex with DNMT1, recruiting DNMT1 to the Foxp1 promoter, which leads to promoter hypermethylation and subsequent inactivation, thereby suppressing Foxp1 transcription and enhancing the sensitivity of colorectal cancer cells to the chemotherapeutic agent capecitabine (16). H3K4me3, the trimethylation of lysine 4 on histone H3, is a crucial epigenetic mark used to study gene expression regulation and epigenetic mechanisms (99, 100). In studies of bone marrow-derived mesenchymal stem cells (BMSCs), circFoxp1 has been shown to recruit KDM5B to suppress PTEN expression. CircFoxp1 facilitates the binding of KDM5B to the PTEN promoter, resulting in reduced H3K4me3 occupancy on the PTEN promoter, thereby inhibiting PTEN transcription and promoting elevated expression of RUNX2, OCN, and OPN, which enhances BMSC proliferation and osteogenic differentiation (14). Thus, circFoxp1, through its epigenetic regulation, particularly via DNA methylation and histone H3K4me3 modifications, significantly influences gene expression and cellular behaviors.

Translation, executed by ribosomes, involves initiation, elongation, termination, and ribosomal recycling (101). CircRNA translation can produce novel proteins or isoforms with new physiological functions (102). Additionally, circRNAs with open reading frames (ORFs) can undergo rolling circle amplification in an internal ribosome entry site (IRES)-independent manner, resulting in production rates that are up to one hundred times higher than those of linear transcripts (103). Wang et al. discovered that circFOXP1 inhibits the progression of intrahepatic cholangiocarcinoma (ICC) by encoding a novel protein, circFOXP1-231aa (46) (as shown in Figure 2F ). Although both circFOXP1 and circFOXP1-231aa are associated with the FOXP1 gene, circFOXP1-231aa does not affect FOXP1 gene expression but rather interacts with different molecules through distinct pathways to influence cellular functions. Specifically, circFOXP1-231aa interacts with OTUD4, which regulates the stability of the NCOA4 protein through deubiquitination. This interaction enhances ferroptosis in ICC cells and suppresses ICC recurrence. The efficiency of circRNA translation and its ability to produce novel proteins make it a focal point of research. The study of circFOXP1-231aa highlights how circRNAs, through protein translation, can interact with key molecules to impact cancer progression and recurrence.

The PI3K/AKT signaling pathway is a highly conserved signaling network in eukaryotic cells that promotes cell survival, growth, and cell cycle progression (104). Wu et al. (51) found that circFOXP1 activates the PI3K/AKT/mTOR signaling pathway by regulating the miR-338-3p/ETS1 axis, thereby enhancing the proliferation, invasion, and migration of colorectal cancer cells. Specifically, their research demonstrated that inhibition of miR-338-3p significantly increased the expression levels of p-AKT and p-mTOR proteins, while knockdown of circFOXP1 could reverse this effect. Furthermore, overexpression of ETS1 also elevated the levels of p-AKT and p-mTOR proteins, without significantly affecting the total levels of AKT, mTOR, or β-actin. These findings highlight the crucial role of circFOXP1 in colorectal cancer, particularly in its regulation of the PI3K/AKT/mTOR signaling pathway via the miR-338-3p/ETS1 axis. Additionally, Xin et al. (14) discovered that circFOXP1 activates the PI3K/AKT pathway by suppressing the expression of PTEN. Remedial experiments using insulin-like growth factor 1 (IGF-I) restored the inhibited proliferation and differentiation of BMSCs caused by circFOXP1 knockdown. This indicates that circFOXP1 plays a critical role in regulating BMSC proliferation and differentiation through the PI3K/AKT pathway. Overall, these findings suggest that circFOXP1 exerts extensive biological functions in various diseases through its regulation of the PI3K/AKT signaling pathway.

The Wnt signaling pathways are essential regulators of cellular processes such as growth, differentiation, and migration, and are of significant importance in developmental biology and cancer research (105). These pathways are primarily divided into canonical (or β-catenin-dependent) and non-canonical (or β-catenin-independent) pathways (106). Research has revealed that the expression of circFOXP1 is downregulated upon reprogramming mesenchymal stem cells (MSCs) into human induced pluripotent stem cells (hiPSCs). Concurrently, the RNA levels of WNT5A, ROR2, PIK3CA, and NRAS are notably decreased. Moreover, the expression of genes involved in the non-canonical Wnt pathway, such as the Wnt5a ligand and Fzd1 co-receptor, is suppressed, while mRNA levels of Wnt3a ligand, Lrp6, and Fzd7 receptors, which are components of the canonical Wnt pathway, are significantly upregulated (90). In MSCs, elevated circFOXP1 levels sustain the activity of the non-canonical Wnt pathway, thereby attenuating the function of the canonical Wnt pathway. Conversely, in hiPSCs, the reduced abundance of circFOXP1 allows miR-17-3p and miR-127-5p to mediate the inhibition of the non-canonical Wnt pathway, thereby enhancing the transmission of endogenous canonical Wnt signals. Thus, circFOXP1 plays a pivotal role in modulating Wnt signaling pathways and influencing cellular fate transitions.