Bicaudal‑C1 in Cancer: Molecular Mechanisms and Therapeutic Strategies Integrating Chinese and Western Medicine

Abstract

Bicaudal-C homolog 1 (BICC1) is an essential RNA-binding protein that plays a significant role in cellular signaling and gene expression regulation. Recent research has linked the BICC1 gene to the initiation and advancement of tumors. Current investigations primarily aim to elucidate its structural characteristics and functional roles, while its precise involvement in tumorigenesis and its viability as a therapeutic target are still being explored. This review delves into the structure and functions of BICC1, emphasizing its participation in tumor cell growth, programmed cell death, epithelial-mesenchymal transition (EMT), blood vessel formation, maintenance of stem cells, and chemoresistance. Furthermore, it examines progress in developing drugs that target BICC1 for cancer therapy and evaluates the potential advantages of traditional Chinese medicine in mediating anti-tumor effects through BICC1 modulation, offering perspectives for future targeted treatment strategies.

Introduction

Cancer poses a significant global health challenge, with nearly 20 million new diagnoses and around 9.7 million fatalities reported in 20221 Conventional treatments like chemotherapy and radiotherapy often yield limited results and come with considerable side effects, prompting a shift towards targeted therapies in cancer management.2 While these targeted approaches offer benefits such as accuracy and reduced harm to healthy tissues, they are hindered by issues like insufficient targets and the emergence of drug resistance.3 BICC1 (Bicaudal-C1), an essential RNA-binding protein initially identified in Drosophila,4 is linked to several cancer-promoting traits, including enhanced tumor cell growth, resistance to apoptosis, epithelial-mesenchymal transition (EMT), angiogenesis, preservation of stem cell characteristics, and chemoresistance,5–8 positioning it as a valuable target for treatment. Despite initial investigations into how BICC1 contributes to cancer development and progression, its precise roles in different cancer types remain poorly understood. Additionally, the development of drugs aimed at BICC1 encounters significant obstacles, and the use of current medications is fraught with limitations. This research utilized databases such as CNKI, PubMed, and Web of Science, including studies that offered clear insights into molecular mechanisms or experimental validation, while excluding those that merely discussed overall efficacy without addressing BICC1’s specific roles or identifying particular targets or pathways. The study details the structure, biological functions, and involvement of BICC1 in cancer, reviews recent advancements in drug development targeting this protein, and highlights the unique potential of traditional Chinese medicine (TCM) and natural products in modulating BICC1. The goal is to synthesize these insights to propose innovative strategies for tumor-targeted therapies that leverage BICC1 regulation and TCM interventions.

Structure, Function, and Cancer Genome Variation of BICC1

BICC1 research spans over 30 years. It began with the KH domain of Bic‑C in Drosophila that regulates embryonic development, advanced to Bicc1 mutations in mammals associated with nephropathy, and progressed to the association of the FGFR2‑BICC1 fusion gene with cancer. It is now recognized as a prognostic marker and a key molecule in chemoresistance in gastric cancer. Recently, studies on the liquid–liquid phase separation (LLPS) mechanism have expanded our understanding of BICC1’s roles in mRNA metabolism and tumor progression (Figure 1).8–15 BICC1 belongs to the Bicaudal‑C family, which comprises three KH domains (KH1–KH3), two KH‑like domains (KHL1–KHL2), and one SAM domain arranged from the N‑terminus to the C‑terminus (Figure 1).6–8,16–18 KH2 specifically recognizes cis‑regulatory elements in the 3′‑UTR of target mRNAs, such as AU‑rich sequences. KHL domains maintain protein conformation, whereas the SAM domain mediates homomultimerization and LLPS. BICC1 represses translation via two mechanisms: it either recruits the CCR4–NOT complex to remove the poly(A) tail, or cooperates with miRISC to achieve post‑transcriptional silencing.19–23 These processes depend on KH2‑mediated recognition and, driven by LLPS, sequester effector complexes within P‑bodies or stress granules, enabling precise spatiotemporal regulation.24–26 Notably, BICC1 functions in a context‑dependent manner. While it is regarded as a canonical translational repressor, it exhibits bidirectional regulatory activities under specific conditions. For instance, during embryonic left–right axis formation, Bicc1 switches its regulation of dand5 mRNA from stabilization to translational repression.27 In tumors, BICC1 promotes the progression of gastric, pancreatic, ovarian, and other cancers by stabilizing mRNAs such as PRRX1 and IDO1, or facilitating the translation of specific target mRNAs.6–8 Collectively, BICC1 is not merely a translational repressor; it exhibits bidirectional regulatory potential, swinging between inhibitory and activating roles depending on cell type, signaling context, and protein interaction networks.

Figure 1.

Timeline of BICC1 research and schematic of the protein structure. (A) Research timeline (1986–2024). Key milestones are highlighted, including the discovery of BICC1 in fruit flies, the identification of vertebrate homologs, the elucidation of its role in kidney development, and its involvement in tumorigenesis and tumor progression. (B) Schematic diagram of BICC1 protein domains. From the N-terminus to the C-terminus: KH1 (red), KH2 (green), and KH3 (blue) are responsible for recognizing cis-elements in the 3’-UTR of target mRNAs; KHL1 (yellow) and KHL2 (light purple) assist in RNA binding and structural stability; the SAM domain (blue-purple) mediates homomultimerization and liquid-liquid phase separation; and the IVS spacer region (gray) connects the domains and isolates their functions. (Created in BioRender.com).

The functional diversity of BICC1 suggests that it may exert multiple roles in tumorigenesis and progression. Genomic variations in BICC1 further reveal an additional layer of oncogenic mechanisms. Databases including TCGA, GDC, and COSMIC document diverse somatic mutations in BICC1. Among these, the FGFR2–BICC1 fusion gene, a structural variant, exhibits the greatest clinical translational potential.26,28 This fusion arises from an approximately 58 Mb intrachromosomal inversion on chr10q. It has a prevalence of 9.7% in intrahepatic cholangiocarcinoma29 and accounts for 10–15% of all FGFR2 fusion events.30,31 Functional studies have confirmed the oncogenic activity of this fusion, and carriers are likely to benefit from targeted therapy with FGFR inhibitors.32,33 However, these prevalence data are derived from RNA‑NGS assays, which have limited sensitivity for detecting DNA rearrangements and may result in false‑negative findings. Regarding insertions and deletions (indels), COSMIC v100 records an overall BICC1 mutation frequency of approximately 4.79%, with frameshift mutations predominating. Representative examples include T755Hfs11 within the SAM domain and I566Sfs5 near the KH2 domain. While these mutations may impair RNA binding or protein–protein interactions, direct evidence for their tumor‑driving capacity remains lacking. In contrast to somatic variants, germline variations in BICC1 show no definitive association with cancer susceptibility. No significant malignancy‑associated signals have been identified in the GWAS Catalog. Germline variants recorded in ClinVar are primarily linked to Mendelian disorders such as CAKUT and exhibit extremely low population frequencies. Collectively, somatic variants of BICC1, particularly FGFR2 fusions and amplifications, confer clear oncogenic significance. In contrast, common germline variants lack GWAS/PheWAS evidence supporting their utility as cancer susceptibility markers.

The Role of BICC1 in Tumorigenesis and Progression

Abnormal overexpression of BICC1 serves as a central driver of tumorigenesis and progression. Its oncogenic effects are exerted via synergistic regulation of multiple signaling pathways: promoting tumor cell proliferation and invasive potential; mediating tumor angiogenesis and the establishment of an immunosuppressive microenvironment; and sustaining cancer stem cell properties while conferring therapeutic resistance. These concerted mechanisms collectively drive malignant progression. Accumulating data demonstrate that BICC1 overexpression in diverse malignancies, including pancreatic cancer, cholangiocarcinoma, and gastric cancer, is significantly correlated with enhanced invasiveness, metastasis, poor prognosis, and clinical chemoresistance.8,34,35

BICC1 and Tumor Proliferation and Apoptosis

Abnormal activation of cell proliferation and apoptosis pathways represents a core hallmark of malignant tumors.36 BICC1 exerts pro‑proliferative and anti‑apoptotic effects across multiple cancer types via distinct molecular mechanisms. In cholangiocarcinoma, a chromosomal translocation between fibroblast growth factor receptor 2 (FGFR2) and BICC1 generates the FGFR2–BICC1 fusion gene.34 The resulting fusion protein undergoes constitutive activation of the FGFR2 kinase domain and continuously phosphorylates FRS2,5 synergistically triggering two key oncogenic cascades. The first is the PI3K‑AKT‑mTOR pathway: phosphorylated FRS2 allosterically activates PI3K‑p110,37 drives the conversion of PIP2 to PIP3,38 and recruits and phosphorylates AKT.39 Activated AKT suppresses apoptosis by inhibiting BAD/Caspase‑9 activity and enhances mTORC1‑mediated metabolic reprogramming.40,41 The second is the Ras‑MAPK pathway,13 where the FRS2‑Ras complex initiates the Raf‑MEK‑ERK signaling cascade.42 Upon nuclear translocation, ERK upregulates anti‑apoptotic proteins and represses pro‑apoptotic factors.43 This fusion‑driven signaling promotes tumor progression through metabolic remodeling and apoptotic resistance, and can be targeted clinically by FGFR inhibitors such as pemigatinib.44 In oral cancer, low expression of miR‑199b‑5p/miR‑101‑3p relieves translational repression of BICC1, leading to aberrant protein accumulation, enhanced proliferation, and suppressed apoptosis; this effect can be reversed by overexpression of the corresponding microRNAs.45 Unlike the mechanism in cholangiocarcinoma, this process does not involve kinase fusions, reflecting tumor‑specific regulatory differences. In gastric cancer, BICC1 binds to and stabilizes PRRX1 mRNA via its KH domain; elevated PRRX1 subsequently activates the MAPK pathway, upregulating Survivin and Bcl‑2 to promote proliferation and inhibit apoptosis,6 a mechanism independent of FGFR2 fusions. Collectively, these findings demonstrate that BICC1 acts as a broad‑spectrum oncoprotein, exerting pro‑proliferative and anti‑apoptotic functions via fusion kinase activation, miRNA downregulation, and the PRRX1‑MAPK axis across diverse malignancies. Notably, the PRRX1‑MAPK axis also contributes to epithelial–mesenchymal transition (EMT) (detailed in Section 3.2), indicating BICC1’s synergistic roles in proliferation, survival, and metastasis (Figure 2).

Figure 2.

Schematic overview of BICC1-mediated mechanisms in tumorigenesis and progression. BICC1 promotes tumor development through four interconnected pro-tumorigenic processes: Proliferation and apoptosis: activation of the PI3K/AKT and MAPK pathways, leading to upregulation of Survivin and Bcl-2. Epithelial-mesenchymal transition (EMT): stabilization of PRRX1 mRNA, activation of the TGF-β/Smad and PI3K/AKT pathways, and subsequent upregulation of ZEB1. Angiogenesis: upregulation of ET-1 via the TRIM29-BICC1-VEZF1 axis, promoting neovascularization. Chemoresistance: mediation through the IDO1/Kyn/AhR “metabolism-stemness-immunity” axis and the SETBP1/SET/PP2A axis.

Notes: “In the diagram, the solid black arrow (↑) indicates promotion or activation, the black T-shaped symbol (⊥) indicates inhibition, the red upward arrow (↑) indicates upregulation of expression or activity, and the blue downward arrow (↓) indicates downregulation”. (Created in Bio Render.com).

BICC1 and Epithelial-Mesenchymal Transition (EMT)

Epithelial-mesenchymal transition (EMT) is a key process in tumor metastasis,46 which causes cells to lose adhesion and polarity and acquire migratory and invasive abilities.36,47 BICC1 is a core regulator of this process and drives EMT through the synergistic activation of TGF-β/Smad and PI3K/AKT signaling pathways.48–50 In the TGF-β/Smad pathway, BICC1 stabilizes Smad2/3 mRNA, promotes its phosphorylation and the formation of transcription complexes, and activates ZEB1.51 In the PI3K/AKT pathway, BICC1 inhibits GSK-3β,12 stabilizes β-catenin and enhances its binding to TCF4,52,53 thereby enhancing the transcriptional activity of ZEB.54 As a core transcription factor, ZEB1 inhibits E-cadherin, promotes N-cadherin and vimentin expression, and ultimately induces EMT.55 Studies have shown35 that increased BICC1 levels are significantly associated with decreased E-cadherin expression and increased lymph node metastasis in gastric cancer. Knockdown of BICC1 reverses EMT characteristics and inhibits tumor cell invasion and migration. In addition, the hypoxic environment promotes BICC1 overexpression through hypoxia-inducible factor-1α (HIF-1α), which further aggravates the EMT process, especially leading to a significant increase in ZEB1 levels. As previously described (see Section 3.1 for details), BICC1 activates the MAPK pathway by stabilizing PRRX1 mRNA, which similarly induces N-cadherin/vimentin and inhibits E-cadherin.6 In vitro and in vivo experiments confirmed that PRRX1 knockdown reverses the EMT effect, and PRRX1 knockdown inhibits BICC1-mediated lung metastasis. In clinical samples, the expression levels of PRRX1 and BICC1 are positively correlated, and patients with high co-expression have the worst prognosis. Taken together, BICC1 plays a central role in tumor metastasis through a multi-dimensional regulatory network, making it a potential target for the development of anti-metastatic therapies (Figure 2).

BICC1 and Tumor Angiogenesis

Tumor angiogenesis is a critical step in tumor growth and metastasis.56 Recent studies have revealed a potential regulatory axis involved in angiogenesis, the TRIM29-BICC1-VEZF1 axis: as an E3 ubiquitin ligase, TRIM29 recruits BICC1 to the 3′-UTR of VEZF1 mRNA; BICC1 binds to this region through its KH domain, and the two act synergistically to promote VEZF1 translation efficiency, thereby upregulating VEZF1 protein levels.7,57 VEZF1 (VEGF endothelial cell-specific zinc finger factor 1) is an endothelial cell-specific C2H2-type zinc finger transcription factor known to directly activate transcription from the endothelin-1 (ET-1) promoter.58 As a potent pro-angiogenic factor, ET-1 induces endothelial cell proliferation, migration, and tube formation, and is a key molecule in the angiogenic regulatory network.59 Based on this, it is hypothesized that BICC1 may be indirectly involved in the regulation of tumor angiogenesis through this axis. However, current validation of this pathway in ovarian cancer models primarily focuses on the regulation of stem cell-like characteristics and invasiveness, and no direct experimental evidence supports its role in regulating angiogenesis. Therefore, the direct association between BICC1 and angiogenesis requires further validation through assays of tumor microvessel density, ET-1 expression levels, and angiogenic function. As a potential angiogenesis regulatory pathway, the TRIM29-BICC1-VEZF1 axis offers a new perspective for understanding the biological function of BICC1, but its role still requires experimental clarification (Figure 2).

BICC1 and Chemoresistance

Chemotherapy resistance is a key factor leading to poor treatment outcomes in malignant tumors.60 BICC1 mediates this process primarily through two molecular pathways. In pancreatic cancer, BICC1 functions via the “metabolism-stemness-immunity” axis mediated by IDO1.8 BICC1 binds to the 3′-UTR of IDO1 mRNA through its KH domain, enhancing mRNA stability and upregulating IDO1 protein levels. IDO1 catalyzes the conversion of tryptophan to kynurenine (Kyn), which activates the aryl hydrocarbon receptor (AhR), initiates JAK2/STAT3 signaling, upregulates cancer stem cell (CSC) markers, and inhibits differentiation.61 Simultaneously, Kyn promotes NAD+ synthesis, enhances mitochondrial oxidative phosphorylation (OXPHOS), increases ATP production, reduces reactive oxygen species (ROS), and enhances the anti-apoptotic capacity of CSCs, forming a “metabolism-stemness” coupling. Furthermore, the BICC1-mediated IDO1/Kyn/AhR pathway induces IL-10 secretion and drives macrophage polarization toward the M2-TAM phenotype.62,63 These M2-TAMs, on one hand, secrete TGF-β to inhibit CD8+ T cells and, on the other hand, degrade the extracellular matrix via MMP9, thereby promoting invasion and blocking the penetration of chemotherapeutic agents.64 Clinical data8 show that high BICC1 expression is significantly associated with elevated IDO1 levels, increased M2-TAM infiltration, and shortened progression-free survival. Combined targeting of BICC1 and IDO1 can reverse gemcitabine resistance. It should be noted that these conclusions are primarily derived from a single research group, and independent validation is warranted. In ovarian cancer, BICC1 acts as a functional partner of TRIM29 to participate in the PP2A activity regulatory axis.7 TRIM29 recruits BICC1 to the 3′-UTR of VEZF1 mRNA and promotes VEZF1 translation. The upregulated VEZF1 subsequently activates the SETBP1 gene promoter, forming the SETBP1/SET/PP2A signaling axis, which leads to inhibition of protein phosphatase 2A (PP2A) activity, sustained activation of cell cycle kinases, and enhanced tumor cell proliferation and stem-like characteristics.65 PP2A inactivation is an important mechanism underlying resistance to platinum-based agents, paclitaxel, and gemcitabine in various tumors.66 Therefore, BICC1 may contribute to chemotherapy resistance through this IDO1-independent pathway. In summary, BICC1 influences chemoresistance via two distinct molecular pathways: the “metabolism-stemness-immunity” axis and the PP2A activity regulatory axis. Future studies should further validate the similarities and differences of these mechanisms across different cancer types and evaluate therapeutic strategies combining targeting of IDO1, PP2A, or VEZF1 (Figure 2).

BICC1 as a Biomarker for Cancer Diagnosis and Prognosis

BICC1 is aberrantly overexpressed in a wide range of malignant tumors and strongly correlated with unfavorable clinical outcomes in patients. These findings indicate its potential as a biomarker for cancer diagnosis, treatment guidance and prognostic assessment.

Pan-Cancer Expression Patterns and Prognostic Analysis

To systematically characterize BICC1 expression across malignancies, its mRNA levels were analyzed in 33 cancer types using data from The Cancer Genome Atlas (TCGA). Comparison between tumor tissues and paired adjacent normal tissues revealed significant upregulation of BICC1 in most cancer types (Figure 3, P < 0.05). Notably, marked overexpression was observed in invasive breast carcinoma, lung squamous cell carcinoma, gastric adenocarcinoma and renal cell carcinoma, suggesting that dysregulated BICC1 expression is tightly linked to tumor initiation and progression. Kaplan-Meier survival analysis was further performed to explore the correlation between BICC1 expression and patient prognosis. The results demonstrated that patients with high BICC1 expression had significantly shorter overall survival than those with low expression (HR = 1.35, 95% CI: 1.01–1.82, P < 0.05) (Figure 3), implying that elevated BICC1 acts as a potential risk factor for poor prognosis across pan-cancer cohorts.

Figure 3.

Expression profiles of BICC1 in various malignant tumors and their association with prognosis. (A) Expression differences. Based on TCGA data, BICC1 mRNA levels were significantly higher in tumor tissues than in paired normal tissues across multiple cancer types, including bladder cancer (BLCA), breast cancer (BRCA), cholangiocarcinoma (CHOL), head and neck squamous cell carcinoma (HNSC), renal chromophobe carcinoma (KICH), renal clear cell carcinoma (KIRC), lung squamous cell carcinoma (LUSC), cutaneous melanoma (SKCM), gastric cancer (STAD), thyroid cancer (THCA), and endometrial cancer (UCEC) (*P < 0.05, **P < 0.01, ***P < 0.001). Red: tumor tissues; blue: normal tissues. (B) Survival analysis. Kaplan-Meier analysis based on pan-cancer data from 33 cancer types (KM Plotter) showed that patients in the high BICC1 expression group (red, n = 200) had significantly worse overall survival than those in the low expression group (black, n = 204), with a hazard ratio (HR) of 1.35 (95% CI: 1.01–1.82) and a log-rank P = 0.045. Note: This analysis did not adjust for confounding factors such as tumor purity, clinical stage, or treatment regimens. Due to inherent heterogeneity among different cancer types, these results should be considered exploratory and hypothesis-generating, requiring independent validation in cancer-specific cohorts with uniform treatment protocols. The x-axis represents time (months); numbers below indicate the number of patients at risk at each time point. (C) Pan-cancer expression overview. Schematic diagram illustrating the aberrant expression pattern of BICC1 across multiple human malignant tumors, corresponding to the cancer types analyzed in (A). The circular diagram summarizes BICC1 expression abnormalities in ten representative tumors: breast cancer, carcinoma of the endometrium, thyroid cancer, gastric carcinoma, cutaneous melanoma, lung cancer, renal carcinoma, head and neck squamous cell carcinoma, cholangiocarcinoma (carcinoma of the bile ducts), and bladder carcinoma.

Several limitations of the present analysis should be acknowledged. First, BICC1 can form a negative feedback loop by binding to the 3′-UTR of its own mRNA via the KH domain, so mRNA levels cannot fully reflect protein function. Second, transcriptional upregulation of BICC1 can be driven by upstream regulators such as HIF-1α, indicating that its overexpression may partially represent secondary alterations in the tumor microenvironment or developmental signaling pathways. Third, RNA-Seq exhibits limited sensitivity for detecting DNA structural rearrangements including the FGFR2–BICC1 fusion. In addition, alignment bias and incomplete reference genomes may cause false-negative detection of fusion genes and inaccurate expression quantification. Accordingly, the reported fusion frequencies and expression correlations are likely conservative estimates, and this analysis cannot distinguish the individual contributions of copy number amplification and gene fusions. Fourth, the pan-cancer Kaplan-Meier analysis was affected by multiple biases: heterogeneous baseline survival and non-proportional hazards among different cancer types, information loss caused by median dichotomization, lack of adjustment for tumor purity and clinical covariates, data batch effects, and inconsistent clinical treatment regimens. Furthermore, the prognostic performance of BICC1 varies by mutation type; for instance, FGFR2–BICC1 fusions serve as potent driver alterations in cholangiocarcinoma. Collectively, the results presented in Figure 3 are exploratory and hypothesis-generating, and require independent validation in cancer-specific cohorts with consistent treatment strategies.

Despite the above limitations, integrated evidence from TCGA pan-cancer expression and survival analyses, together with previous reports showing BICC1 overexpression and its association with gemcitabine resistance in pancreatic cancer17 and cholangiocarcinoma,20 supports that BICC1 is a promising therapeutic target and prognostic biomarker. Future work is needed to further dissect its molecular mechanisms and systematically evaluate its clinical translational value in prospective clinical cohorts.

Potential as a Clinical Biomarker

BICC1 expression is significantly upregulated in a variety of malignant tumors, including pancreatic ductal adenocarcinoma (PDAC), cholangiocarcinoma, and gastric cancer, and its expression level correlates with tumor progression, metastasis, and chemotherapy resistance.8,34,35 Notably, in cholangiocarcinoma,13 the FGFR2‑BICC1 fusion gene serves not only as a specific molecular marker for diagnostic subtyping but also as a predictive biomarker to guide targeted therapy with FGFR inhibitors such as pemigatinib.67–69

Prognostic Value

Multiple studies confirm that high BICC1 expression is significantly associated with shorter overall survival (OS) and disease‑free survival (DFS). BICC1 serves as an independent poor prognostic factor in PDAC and gastric cancer.8,35 A recent cohort study involving 85 gastric cancer tissue samples6 further confirms the prognostic value of BICC1: high BICC1 expression is positively correlated with tumor size, depth of invasion, lymph node metastasis, and clinical stage, and overall survival of patients with high BICC1 expression is significantly shorter (P = 0.0373). ROC curve analysis demonstrates its diagnostic value for advanced stage, lymph node metastasis, and deep invasion (AUC = 0.63, 0.72, and 0.86, respectively). Furthermore, BICC1 protein expression is positively correlated with that of its downstream molecule PRRX1, and patients with high co‑expression of BICC1 and PRRX1 have the worst prognosis (P < 0.001), suggesting that combined detection of these two markers may improve the accuracy of prognostic assessment.

Therapeutic Strategies and Research Progress Targeting BICC1

Small-Molecule Drug Intervention Strategies Targeting the BICC1 Signaling Pathway

BICC1 is an RNA-binding protein that binds to target mRNAs to promote their expression and regulate tumor progression. Given the lack of direct inhibitors for BICC1, current therapeutic strategies primarily focus on key upstream and downstream nodes to indirectly block its oncogenic function. FGFR inhibitors, such as the pan-FGFR inhibitor erdafitinib and the selective inhibitor pemigatinib, inhibit downstream PI3K/AKT and MAPK signaling pathways by blocking the kinase activity of the FGFR2-BICC1 fusion protein.69 Among these, pemigatinib has demonstrated therapeutic potential in a Phase II clinical trial for cholangiocarcinoma with FGFR abnormalities.70 HIF-1α inhibitors (such as PX-478 and echinomycin) disrupt the HIF-1α/BICC1/ZEB1 metastatic regulatory axis by interfering with the binding of HIF-1α to the hypoxia response element (HRE) in the BICC1 promoter; PX-478 has completed Phase I trials in solid tumors. ET-1 receptor antagonists block ET-1/ETA receptor signaling driven by the BICC1-TRIM29-VEZF1 axis, thereby inhibiting AKT/MAPK phosphorylation and the expression of pro-angiogenic factors such as VEGF and MMPs, thus antagonizing tumor angiogenesis mediated by this axis. The androgen receptor (AR) antagonist flutamide downregulates BICC1 expression by blocking AR-mediated transcriptional activation of the BICC1 promoter,71 thereby overcoming IDO1-associated chemotherapy resistance; this mechanism has been validated in a pancreatic cancer model. To target BICC1-mediated metabolic reprogramming, IDO1 small-molecule inhibitors reverse tumor resistance by inhibiting the tryptophan-kynurenine metabolic axis. Among these, the competitive inhibitor epacadostat has entered Phase III clinical trials, and the irreversible inhibitor linrodostat is also in the clinical evaluation stage. PP2A activators block the formation of the SET-PP2A complex, restore PP2A activity, and reverse PP2A inhibition at the downstream end of the BICC1 axis, thereby counteracting pancreatic cancer chemoresistance. Furthermore, miRNA-based regulatory strategies utilize molecules such as miR-199b-5p and miR-101-3p to target the 3′-UTR of BICC1 mRNA and inhibit its translation; these have been shown to induce tumor cell apoptosis in oral cancer models (Table 1).

Table 1.

Small-Molecule Drugs Related to BICC1

Small Molecule Types	Name	PubChem CID		Effect on BICC1	Molecular Mechanisms	Model	References	Research Type
FGFR Inhibitors	Erdafitinib (JNJ-42756493)	567462786		Indirectly inhibits BICC1 oncogenic activity by suppressing downstream pathways activated by FGFR fusion proteins	Mek-Erk RAS-MAPK/PI3K-AKT pathway ↓, cancer cell proliferation ↓, apoptosis and cell cycle arrest ↑.	Non-small cell lung cancer, urothelial cancer, esophageal cancer, cholangiocarcinoma	[70,72]	Phase II clinical trial NCT02699606
	Futibatinib	71621331				Patients with advanced solid tumors with FGF/FGFR aberrations	[73,74]	Phase I/II clinical trial NCT01752920
	Debio-1347	66555680				Biliary tract cancer, urothelial carcinoma, and other solid tumors	[75,76]	Phase II clinical trial (NCT03834220)
	Pemigatinib	86705695				Locally advanced or metastatic cholangiocarcinoma	[33,77]	Phase II clinical trial (NCT02924376)
	Infigratinib (BGJ398)	53235510				Cholangiocarcinoma with FGFR 2 fusions or rearrangements	[78,79]	Phase II clinical trial (NCT02150967)
	Derazantinib (ARQ 087)	46834118				Advanced solid tumors with FGFR genetic alterations	[80,81]	Phase I/II clinical trial NCT01752920
	Ponatinib	24826799				Patients with advanced cholangiocarcinoma with FGFR alterations	[81,82]	Phase II clinical trial NCT02265341
HIF1α inhibitors	PX-478	11234794		Invalidates the HIF-1α/BICC1/ZEB1 cascade regulatory axis and reduces BICC1 expression	Translation of HIF-1α protein ↓, HRE binding in BICC1 promoter region ↓	Multiple human tumor xenograft models	[83,84]	Phase I clinical trial NCT00522652
	Spines drug	6857732			Hetero-binding HIF-1 recognizes the core of the sequence 5’-CGTG-3’, HIF-1 and DNA binding ↓	Breast cancer cells, glioma cells	[85,86]	Preclinical studies
	Aminoflavone	389710			Binding specifically to HIF-1α mRNA as well as HIF-1α target gene expression ↓	Breast cancer cell and renal cancer cell lines	[87]	Preclinical studies
	Camptothecins	24360			Form stable Top 1-DNA cleavage complexes to poison Top 1, which produces double-stranded DNA breaks. Translation of the HIF-1α protein ↓	Solid tumors, lymphomas	[88,89]	Phase I/II clinical trial NCT01295697
	2-Methoxyestradiol	-			HIF-1α binds to DNA ↓	Solid tumors	[90,91]	Phase I clinical trial NCT00030095
ET-1 receptor antagonist	Zibotentan (ZD4054)	9910224		Through antagonism ETAR blocking BICC1 TRIM29 - VEZF1 shaft drive downstream promoting angiogenesis ET - 1 signal, thus the functional antagonism shaft mediated angiogenesis procedure.	Blocking BICC1-TRIM29-VEZF1-ET-1 axis signaling, AKT/MAPK phosphorylation ↓, VEGF/MMP-2/9/COX-1/2 expression ↓, angiogenesis and invasion ↓	Ovarian cancer xenograft tumors	[92,93]	Phase II clinical trial 2007–003224-38
	Atrasentan (ABT-627)	159594			By antagonizing the ETA receptor, blocking ET-1 autocrine signaling, VEGF production ↓, and tumor neovascularization ↓	Colon cancer, prostate cancer	[94]	Phase III clinical trial NCT00036556
	Bosentan	104865			Inhibition of ET-1 induced upregulation of VEGF and HIF-1α mediated angiogenic signaling, neovascularization ↓	Breast cancer	[95,96]	Preclinical studies
	Macitentan (ACT-064992)	16004692			Blocking ETA →ETR phosphorylation ↓pVEGFR2/pAkt/pMAPK ↓, endothelial apoptosis ↑, angiogenesis ↓	Ovarian cancer	[97]	Preclinical studies
Androgen receptor antagonists	Flutamide	3397		Downregulation of BICC1 expression	Competitively blocking AR binding to androgens, transcriptional activation of BICC1 promoter by AR ↓	Pancreatic cancer	[98,99]	Preclinical studies
Small molecule inhibitors of IDO1	1MT	L-1MT	-	Indirect inhibition of BICC1-mediated metabolic reprogramming	Tryptophan transport ↓ and IDO1 downstream mTOR/PKC-θ↓	Relapsed or refractory solid tumors	[100]	Phase I study NCT00739609
		D-1MT	405012		Effector T cell proliferation ↑
	Epacadostat	135564890			IDO1 activity ↓, tryptophan metabolism to kynurenine ↓	A wide variety of tumor models	[101]	Phase III clinical trials EUCTR2015-004991-31-SE
	NLG919	66558287		-	IDO1 activity ↓, kynurenine generation ↓	Recurrent advanced solid tumors	[102,103]	Phase I clinical trial NCT02048709
	Linrodostat	121328278		-	High affinity irreversible binding to IDO1, kynurenine generates ↓	Solid tumors	[104,105]	NCT03459222 phase I/II clinical trials
PP2A activation agent	FTY720 (Fingolimod, Gilenya)	107969		Indirect inhibition of PP2A blocking the upstream signal.	Binding to the N-terminal region of the SET protein disrupts the formation of the SET-PP2A complex and restores the physiological activity of PP2A	Pancreatic cancer	[106]	Preclinical studies
miRNA Inhibitors	miR-199b-5p	-		Direct inhibition of BICC1 expression	Binding to the 3’utr region of BICC1 mRNA translation or degrades mRNA↓	Oral cancer	[45]	-
	miR-101-3p	-

Notes: ↑, promotion; ↓, inhibition.

Potential Application of Traditional Chinese Medicines and Natural Products That Regulate BICC1 in Cancer Therapy

Traditional Chinese medicine (TCM) shows great potential in BICC1-targeted cancer therapy. Small-molecule natural products are abundant and exhibit favorable safety profiles. Their compound formulations, leveraging the synergistic effects of multiple components and multiple targets, provide diverse intervention strategies for regulating BICC1. Although no natural products directly targeting BICC1 have been identified to date, a large number of studies have shown that modulating BICC1 or its related pathways can exert significant anticancer effects.

Targeted Intervention of BICC1 by Natural Bioactive Compounds

BICC1 is a key signaling hub protein and plays an important role in the occurrence and development of a variety of tumors. Studies have shown that multiple natural compounds can target BICC1 and its related signaling pathways to inhibit tumor growth, proliferation, and metastasis, and to induce cancer cell death. Molecular docking confirms that these compounds can bind spontaneously to BICC1 (with binding energies below –5 kcal/mol), suggesting their potential as lead compounds for targeting BICC1 (Table 2).

Table 2.

Active Components That Regulate BICC1

Active Ingredients	Primary Classification	CID	Sources	Models	Regulatory Mechanisms	Effects	References
Curcumin	Polyphenols	969516	Turmeric	NSCLC cells A549 and H1299	PI3K/Akt/mTOR pathway ↓, p-Akt /p-mTOR↓, miR-101↑, EZH2 oncogene ↓	It can induce cell apoptosis and inhibit cell proliferation	[107,108]
Saikosaponin B4	Saponins	21637636	Radix bupleuri	Human colon cancer cells	Phosphorylation of PI3K, AKT, mTOR and their mRNA expression ↓, Bax, Caspase-3/9 ↑, Bcl-2 ↓	It induces apoptosis and inhibits proliferation	[109]
Baicalein	Flavonoids	5281605	Scutellaria baicalensis	Breast cancer cells	The Expression of miR-17-5p↓	Up-regulation of tumor suppressor gene expression and tumor suppressive effect	[110]
Osthole	Coumarins	10228	Cnidium monnieri	Human gastric cancer cells	PI3K expression and p-Akt levels are↓, Cyclin B1 and Cdc2 expression is↓, and G2/M phase arrest occurs	The proliferation of gastric cancer cells was inhibited	[111,112]
Raddeanin A	Saponins	174742	RHIZOMA ANEMONES RADDEANAE	NSCLC A549 cells and H1299	p-PI3K, p-AKT, and p-mTOR ↓; Beclin-1 and LC3B ↑	It can inhibit the proliferation and survival of lung cancer cells, and promote cell apoptosis and autophagy	[113]
				HGC gastric cancer cells and SGC-7901-27, SNU-1	MAPK signaling pathway ↑, BAX expression ↑, BCL-2 expression ↓, activation of Caspase-3 and PARP proteins, Beclin-1, ATG5, and LC3B ↑	It can inhibit the proliferation of gastric cancer cells and promote apoptosis and autophagy of gastric cancer cells	[114]
Catechol	Polyphenols	289	Green tea	MCF-7 cells	p-AKT↓, BAD and Caspase-9↑, MCL-1/Bcl-2↓	Reverses apoptotic resistance and promotes apoptosis	[115]
Cucurbitacin B	Terpenoids	5281316	Gourd	NSCLC A549 cells	Reversed cellular morphological changes. p-Smad2/3 and p-AKT ↓, GSK-3β activity ↑, ZEB1 ↓, E-cadherin ↑, N-cadherin and vimentin ↓	It also attenuated cell migration and invasion ability and inhibited EMT of A549 cells	[116]
Galangin	Flavonoids	5281616	Galangal	Gastric cancer cell line SGC-7901	HIF-1α, Snail, Vimentin↓, E-cadherin↑, EMT↓	Adjust HIF - 1 alpha and EMT related factor expression,	[117]
Paeoniflorin	Terpenes	442534	Peony	Cancer of the stomach	NEDD4L mRNA and protein ↑, direct binding of NEDD4L, BICC1 ubiquitination ↑, BICC1 protein ↓, PI3K/AKT activity and EMT process ↓	Inhibiting gastric cancer cell proliferation, migration and PI3K/AKT mediated EMT	[118]
Basil polysaccharide	Polysaccharides	-	Basil	HCC cells	HIF-1α expression ↓, mesenchymal markers β-catenin, N-cadherin, and Vimentin↓, and epithelial markers E-cadherin, VMP1, and ZO-1↑	Alleviate tumor hypoxia and inhibit cell invasion and metastasis	[119]
Emodin	Quinones	3220	Rhubarb	SGC7901 gastric cancer cells	HIF-1α expression ↓, E-cadherin↑	Inhibiting tumor cell proliferation	[120,121]
Evodiamine	Alkaloids	442088	Evodia rutaecarpa	Endometrial cancer is Ishikawa	HIF-1α, Snail, and vimentin ↓; E-cadherin ↑	Adjust HIF - 1 alpha and EMT related factor expression, inhibition of endometrial cancer cells	[122,123]
Epigallocatechin gallate	Polyphenols	65064	Green tea	Colorectal cancer model	IDO1 expression and enzyme activity ↓, kynurenine ↓	Blocking tryptophan metabolism for dog urine glycine, destroy BICC1 mediated metabolic reprogramming and chemotherapy resistance	[124]
Astragaloside IV	Saponins class	13943297	Astragalus	Mouse model of lung cancer	IDO1 mRNA and protein ↓, proportion of regulatory T cells ↓, activity of cytotoxic T lymphocytes ↑	Remove the immune state of tumor microenvironment, enhance the capacity of the body’s immune surveillance and attack the tumor, thereby inhibiting tumor growth and progression	[125]
4-Acetylantroquinonol B	Quinones	112500518	Agaratopsis camphorata	Multiple cancer cell Models	Inhibition of pVEGF, pPI3K, pERK, and p-mTOR, VEGF secretion ↓	Inhibition of new blood vessels form and reduce tumor microvascular density	[126]
Salvianolic acid A	Polyphenols	5281792	Salvia miltiorrhiza	A variety of tumor cell lines	Blockade of ET-1 signaling, EGFR ↑, VEGF expression ↑, angiogenesis ↑	Mediated by inhibiting the ETAR, reduce ET - 1 VEGF and tumor angiogenesis.	[127]

Notes: ↑, promotion; ↓, inhibition.

1) Regulation of cell proliferation and apoptosis: Curcumin107,108 acts through a dual mechanism in lung cancer models: it inhibits the PI3K/AKT/mTOR pathway and upregulates miR-101-3p to reduce BICC1 expression, synergistically inducing apoptosis and autophagy. Saikosaponin B4 (SSB4)109 disrupts the Bcl-2/Bax balance by inhibiting the same pathway and activates the caspase cascade to induce apoptosis in colorectal cancer. Baicalein20,110 indirectly regulates the BICC1 network through its core target miR-17-5p: it inhibits miR-17-5p to upregulate tumor suppressor genes and blocks the PI3K/AKT pathway, while BICC1 acts as a natural antagonist of miR-17 to maintain target gene expression. The two have complementary functions in the miR-17/PI3K/AKT pathway, suggesting that baicalein may cooperate with BICC1 to antagonize the cancer-promoting effect of miR-17. Osthole111,112 mainly shows cell cycle-specific effects in gastric cancer, downregulating the Cyclin B1/Cdc2 complex and inducing G₂/M phase arrest by inhibiting the PI3K/AKT pathway. In addition, the tissue-specific effect of Raddeanin A (RA)113,114 is particularly notable: RA induces apoptosis/autophagy via the PI3K/AKT/mTOR pathway in lung cancer, whereas it activates the p38 MAPK pathway to trigger the same effect in gastric cancer. Catechin115 can reset the apoptotic threshold, inhibit the PI3K/AKT pathway, and regulate Bcl-2 family proteins to downregulate Mcl-1/Bcl-2 and increase the Bax/Bcl-2 ratio, effectively reversing apoptosis resistance in tumor cells.

2) Reversing the EMT process: As a key regulator of EMT, BICC1 can be directly or indirectly inhibited by natural small molecules. Cucurbitacin B116 disrupts the β-catenin/TCF4-ZEB1 transcription complex by simultaneously inhibiting the TGF-β/Smad and PI3K/AKT/mTOR pathways in lung cancer, thereby blocking EMT-driven metastasis. Overexpression of BICC1 induced by a hypoxic microenvironment can be directly targeted by galangin, which blocks the TGF-β/Smad and PI3K/AKT pathways and inhibits ZEB1 activity by suppressing HIF-1α-mediated BICC1 expression in gastric cancer.117 Paeoniflorin (PF) shows a unique mode of action:118 it promotes BICC1 ubiquitination and degradation by upregulating the E3 ubiquitin ligase NEDD4L in glioma; in gastric cancer, it inhibits EMT mediated by the PI3K/AKT pathway. In addition, some molecules indirectly affect BICC1 by regulating HIF-1α. For example, basil polysaccharide downregulates BICC1 expression by inhibiting HIF-1α.119 Emodin120,121 and evodiamine122 can reverse EMT by upregulating E-cadherin and downregulating Snail/Vimentin via this pathway.

3) Reprogramming the immune microenvironment: BICC1-mediated immune evasion can be reversed by specific small molecules. Epigallocatechin-3-gallate (EGCG)123 reverses chemoresistance by disrupting BICC1-driven tryptophan metabolic reprogramming through dose-dependent inhibition of IDO1 expression.124 Astragaloside IV exhibits dual immunomodulatory functions: on one hand, it inhibits IDO1 expression to block the transcriptional enhancement of IDO1 by BICC1; on the other hand, it reshapes the immune cell balance by reducing regulatory T cell (Treg) infiltration and enhancing cytotoxic T lymphocyte (CTL) activity, thereby synergistically reversing the tumor immunosuppressive microenvironment.125

4) Inhibition of tumor angiogenesis: BICC1-mediated tumor angiogenesis can be interfered with by naturally derived multi-target small molecules. Salvianolic acid A (Sal A) blocks downstream signaling of the ETAR and BICC1-TRIM29-VEZF1 axis and inhibits endothelial cell proliferation, migration, and tube formation.127 4-Acetylantroquinonol B (4-AAQB) acts on the VEGFR2/PI3K/ERK/mTOR pathway to block the VEGF-induced angiogenesis cascade.126 The two compounds act synergistically to reduce tumor microvessel density.

To validate the direct binding of natural bioactive compounds to BICC1 and to screen for potential lead compounds, molecular docking was performed for virtual screening. Semi‑flexible docking was carried out using AutoDock Vina, with the AlphaFold predicted model of human BICC1as the receptor and 14 natural small molecules as ligands (see Supplementary Information: Appendix S1 for detailed methods, and Supplementary Table S1 for binding parameters). Molecular docking analysis shows that multiple natural compounds can specifically bind to the active pocket of the BICC1 protein (Figure 4). Among them, saikosaponin B4 (SSB4), cucurbitacin B, Raddeanin A, and cinobufagin exhibit the strongest binding potential and are identified as the most promising lead compounds. Calculation of binding free energy (ΔG) confirms that the binding of these compounds to BICC1 is spontaneous (ΔG < 0). The more negative the ΔG value, the stronger the binding affinity; SSB4 has the lowest ΔG value, indicating the strongest binding ability. Mechanistic analysis shows that the ligands stabilize the complex primarily by forming specific hydrogen bond networks with key polar residues such as Asp909, Gln902, and Asn934, while hydrophobic regions within the active pocket provide synergistic interactions. These docking results reveal key characteristics of BICC1 as a drug‑targetable protein: the structure of its active pocket is well defined, and BICC1 can bind a variety of structurally diverse natural compounds with high affinity and specificity, forming stable interactions. This finding lays an important structural foundation for the development of BICC1‑targeted inhibitors.

Figure 4.

Molecular docking models of BICC1 with active natural compounds. Using the AlphaFold predicted model of human BICC1 as the receptor and representative natural compounds (saikosaponin B4, cucurbitacin B, raddeanin A, and cinobufagin) as ligands, semi-flexible docking was performed with AutoDock Vina. The figure shows these compounds binding to the active pocket of BICC1, stabilized mainly by hydrogen bond networks and hydrophobic interactions. The binding free energy (ΔG) was less than 0 for all compounds, indicating spontaneous binding, with saikosaponin B4 showing the strongest affinity.

Overall Regulatory Potential of Multiple Pathways of Traditional Chinese Medicine Compounds

Traditional Chinese medicine formulas leverage their multi-component synergistic advantages to exhibit comprehensive effects on BICC1-related pathways: Yanghe Decoction128 inhibits the proliferation of breast cancer MCF-7 cells and induces apoptosis, with mechanisms involving inhibition of PI3K/Akt signaling pathway activation (reducing PI3K and Akt phosphorylation, and upregulating PTEN), suggesting it may synergistically regulate BICC1 expression. The Huangqi Baizhu Formula129,130 reduces HIF-1α and MMP2 mRNA expression in an in vivo lung cancer model, significantly reducing tumor metastasis sites, indicating that it exerts anti-metastatic effects by inhibiting the HIF-1α/MMP2 axis and EMT. The modified Tongyou Decoction131,132 reduces the expression of mTOR, HIF-1α, and VE-cadherin proteins in esophageal cancer cells, suggesting that it inhibits metastasis by affecting EMT-related factors, such as VE-cadherin, through the mTOR/HIF-1α pathway. The Yiai Decoction133 inhibits the formation of vascular mimicry (VM) in colorectal cancer cells in a dose-dependent manner by suppressing the HIF-1α/EMT pathway, potentially indirectly regulating BICC1 activity. Compound Kushen Injection134 regulates the vascular microenvironment by reducing VEGF/ET-1, promoting vascular maturation increased VMI, decreased MVD, and reducing vascular distribution, thereby exerting anti-liver cancer effects in mouse xenografts. As an upstream regulatory protein in this pathway, BICC1 may also be influenced by this mechanism. Buzhong Yiqi Decoction135 may indirectly inhibit BICC1-related tumor immune escape by enhancing CD8+ T cell activity and suppressing Treg cells to improve the immunosuppressive microenvironment. Jin Fu Kang136 significantly inhibits tumor IDO1 expression and activity (at both the protein and gene levels) in a mouse lung cancer model transfected with the IDO1gene, thereby affecting the immune microenvironment (Table 3).

Table 3.

Regulation of BICC1 by Traditional Chinese Medicine Compounds

Traditional Chinese Medicine Compound	Composition	Model	Regulatory Mechanisms	Effects	Impact on BICC1	References
Jiawei Yanghe Decoction	Rehmanniae Radix Praeparata, Chinese Ephedra Herb, Deerhorn Glue, White Mustard Seed, cinnamon, Licorice Roots, Northwest Origin, Ginger charcoal	Breast cancer cells	P-AKT, p-PI3K↓, the expression of PTEN↑;	The cell proliferation activity is inhibited, cell apoptosis rate increases	Through the inhibition of PI3K/Akt signaling pathways regulating BICC1 together	[128]
Huangqi Baizhu Formula	Milkvetch Root, Macrocephalae Rhizoma s	LoVo, HCT - 116 cells, lung cancer metastasis in mice model	HIF-1α and MMP2 mRNA↓, Tumor metastases in nude mice ↓	Inhibition of EMT, reduce metastatic disease	HIF - 1 alpha/EMT pathways through indirect regulation BICC1 activity	[129,130]
Modified Tongyou Decoction	Peach Seed, Safflower, Skunk Bugbane Rhizome, Adhesive Rehmannia Root, Tuber prepared rehmannia root, the body of Chinese angelica, Glycyrrhizae Radix Et Rhizoma	SD rat Esophageal cancer cells	MTOR, HIF-1α, VE- cadherin ↓	Reduce esophageal cancer cell metastasis	Through the mTOR/alpha channel indirect regulation BICC1 HIF - 1	[131,132]
Yiai Decoction	Mongolian Milkvetch Root, Largehead Atractylodes Rhizome, Chinese Actinidia Root, Blue Turmeric Rhizome, Chinese Waxgourd Semen	Colorectal cancer cells	HIF-1α/EMT pathway ↓, Colorectal cancer cell growth and the formation of angiogenesis mimicry (VM) ↓	Inhibit the formation of large intestine cancer VM to inhibiting tumor angiogenesis	HIF - 1 alpha/EMT pathways through indirect regulation BICC1 activity	[133]
Compound Kushen Injection	Sophora flavescensRhizoma Heterosmilacis Japonicae	Liver transplantation in mice tumor model	VEGF expression↓, promotes vascular maturation, VMI↑, MVD↓, reduced vascular distribution	Liver transplantation in mice tumor model	By reducing the VEGF/indirect regulation BICC1 ET - 1	[134]
Buzhong YIqi Decoction	Radix astragali, Radix codonopsis pilosulae, Radix angelicae sinensis, Radix glycyrrhizae, Cimicifugae rhizoma, Radix bupleuri, Atractylodes macrocephala, Pericarpium citri reticulatae;, Rhizoma Sparganii, Rhizoma Curcumae	Immunosuppressive mice model	CD8+ T-cell activity ↑, Treg cells ↓, regulation of M1/M2 macrophage differentiation	Inhibition of tumor growth and metastasis, improve immunosuppression microenvironment	Indirect inhibition BICC1 related to tumor immune escape	[135]
Jinkangfu	Mongolian Milkvetch Root, Coastal Glehnia Root, Dwarf Lilyturf Root Tuber, Glossy Privet Fruit, Common Macrocarpium Fruit, Fiveleaf Gynostemma Herb or Root, Common Fenugreek Seed, Selaginella doederleinii Hieron, Chinese Sage Herb, Chinese Manyleaf Paris Rhizome, Cochinchinese Asparagus Root Tuber	Lung cancer in mice IDO1 gene transfection	IDO1 activity and expression ↓, modulating the immune microenvironment	Inhibition of tumor immune escape	Indirect inhibition BICC1 related to tumor immune escape	[136]

Notes: ↑, promotion; ↓, inhibition.

Conclusion and Prospect

Cancer remains a major global public health burden. As a core regulatory hub involved in RNA metabolism, tumor stemness, and chemoresistance, BICC1 exhibits promising potential for prognostic assessment and targeted therapeutic development. In this study, molecular docking was performed to screen traditional Chinese medicine active ingredients with high binding affinity for BICC1, among which saikosaponin B4 was identified as a candidate compound. These findings provide preliminary computational evidence supporting the targetability of BICC1 by natural products, suggesting that BICC1-targeted natural drugs may effectively reverse tumor stemness and chemotherapy resistance. Although BICC1 has been validated as a viable therapeutic target, the direct development of BICC1-specific small-molecule inhibitors still faces considerable challenges.

Direct inhibitor development against BICC1 is hindered by three major limitations. First, the KH domain-mediated protein–RNA interface is flat and highly hydrophobic, rendering it difficult for conventional small molecules to achieve effective competitive binding. Second, BICC1 engages in complex intermolecular interactions through multiple functional domains, which cannot be completely blocked by single-target inhibitors. Third, BICC1 is essential for normal renal development; systemic pharmacological inhibition of BICC1 may therefore cause unavoidable nephrotoxicity. Accordingly, targeting BICC1 downstream signaling cascades represents a more feasible and safer therapeutic strategy.

Targeting downstream pathways offers several distinct advantages. First, key downstream nodes, including the PI3K/AKT, MAPK, IDO1, and PP2A axes, have mature clinically available inhibitors and auxiliary biomarkers (eg the kynurenine/tryptophan ratio and FGFR fusion status), enabling rapid therapeutic sensitivity verification, precise patient stratification, and accelerated clinical development. Second, multiple inhibitors targeting these pathways have already been approved for other malignancies, allowing drug repurposing to reduce developmental costs and minimize safety risks. Third, since BICC1 concurrently activates multiple oncogenic signaling networks, multi-node or multi-kinase combinatorial targeting can thoroughly block BICC1-driven oncogenic signaling and prevent compensatory pathway reactivation. Fourth, the physiological renal functions of BICC1 may be independent of its tumor-specific regulatory pathways, such as the IDO1-kynurenine axis. Selective suppression of oncogenic downstream cascades is expected to maintain antitumor efficacy while reducing nephrotoxicity. Collectively, combined or sequential targeting of downstream effectors, including IDO1 inhibitors, FGFR inhibitors, and PP2A activators, represents a safer and more practical therapeutic strategy at the current stage.

Nevertheless, two critical bottlenecks remain to be addressed. On the one hand, the pan-cancer regulatory mechanisms of BICC1-driven oncogenesis are not fully elucidated, which hinders the development of universal BICC1-based biomarkers. On the other hand, highly efficient and selective BICC1-targeting small-molecule tools are currently lacking, and computationally predicted candidate compounds such as saikosaponin B4 require rigorous experimental validation.

To overcome these limitations and facilitate the clinical translation of BICC1-targeted therapy, future research directions should focus on the following aspects. First, multi-omics integration combined with patient-derived xenograft (PDX) and tumor organoid models is warranted to systematically characterize BICC1-mediated regulation of the Wnt/β-catenin and EMT pathways, as well as the conserved mechanisms underlying BICC1-driven chemoresistance across cancer types. Second, artificial intelligence-assisted screening and proteolysis-targeting chimera (PROTAC) technology should be applied based on the structural features of the BICC1 RNA-binding domain to develop highly selective BICC1 degraders. Meanwhile, surface plasmon resonance (SPR) and other biochemical assays are required to verify the direct binding activity of candidate molecules and their regulatory effects on RNA metabolism, thereby optimizing the structure–activity relationship. Third, the multi-component synergistic mechanisms of traditional Chinese medicine formulas targeting BICC1 should be clarified, and corresponding activity-based quality control standards need to be established. Fourth, preclinical efficacy and safety evaluations of single-agent or combinatorial therapeutic strategies should be conducted using BICC1-overexpressing tumor models. Furthermore, BICC1-based ctDNA liquid biopsy assays can be developed and validated for pan-cancer diagnosis and prognostic monitoring. For patients with BICC1-positive advanced malignancies, rational “targeted therapy plus chemotherapy” combination regimens should be designed, with clinical efficacy evaluated based on objective response rates and drug resistance reversal efficiency.

Funding Statement

This work was supported by Lanzhou Municipal Science and Technology Bureau Project (No.2025-2-3); Gansu Provincial Silver-Age Experts Studio (Provincial Party Committee Talent Group [2025] No. 4); Construction Project of High-Level Talent Studios in Traditional Chinese Medicine (Zhang Zhiming, Gansu Association for Science and Technology [2021] No. 125); Gansu University of Traditional Chinese Medicine Postgraduate Innovation and Entrepreneurship Fund Project (2026CXCY-027); Gansu University of Traditional Chinese Medicine Postgraduate Innovation and Entrepreneurship Fund Project (2026CXCY-033).

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Abbreviations

BICC1, Bicaudal-C Homolog 1; EMT, Epithelial-Mesenchymal Transition; TCM, Traditional Chinese Medicine; KH, K Homology domain; KHL, KH-Like domain; SAM, Sterile Alpha Motif; LLPS, Liquid-Liquid Phase Separation; CCR4, Carbon Catabolite Repressor 4; NOT, Negative on TATA; miRISC, miRNA-Induced Silencing Complex; PRRX1, Paired Related Homeobox 1; IDO1, Indoleamine 2,3-Dioxygenase 1; FGFR2, Fibroblast Growth Factor Receptor 2; TCGA, The Cancer Genome Atlas; GDC, Genomic Data Commons; COSMIC, Catalogue of Somatic Mutations in Cancer; NGS, Next-Generation Sequencing; GWAS, Genome-Wide Association Study; PheWAS, Phenome-Wide Association Study; CAKUT, Congenital Anomalies of the Kidney and Urinary Tract; FRS2, Fibroblast Growth Factor Receptor Substrate 2; PI3K, Phosphoinositide 3-Kinase; AKT, Protein Kinase B; mTOR, Mechanistic Target of Rapamycin; MAPK, Mitogen-Activated Protein Kinase; Ras, Rat Sarcoma Virus GTPase; Raf, Rapidly Accelerated Fibrosarcoma; MEK, Mitogen-Activated Protein Kinase; ERK, Extracellular Signal-Regulated Kinase; miR, MicroRNA; ZEB1, Zinc Finger E-Box Binding Homeobox 1; TGF-β, Transforming Growth Factor-β; Smad, Sma- and Mad-Related Protein; GSK-3β, Glycogen Synthase Kinase 3 Beta; TCF4, Transcription Factor 4; HIF-1α, Hypoxia-Inducible Factor-1α; TRIM29, Tripartite Motif-Containing Protein 29; VEZF1, VEGF Endothelial Cell-Specific Zinc Finger Factor 1; ET-1, Endothelin-1; VEGF, Vascular Endothelial Growth Factor; MMP, Matrix Metalloproteinase; MMP9, Matrix Metalloproteinase 9; Kyn, Kynurenine; AhR, Aryl Hydrocarbon Receptor; JAK2, Janus Kinase 2; STAT3, Signal Transducer and Activator of Transcription 3; CSC, Cancer Stem Cell; OXPHOS, Oxidative Phosphorylation; ATP, Adenosine Triphosphate; ROS, Reactive Oxygen Species; TAM, Tumor-Associated Macrophage; SETBP1, SET Binding Protein 1; SET, SET Nuclear Proto-Oncogene; PP2A, Protein Phosphatase 2A; OS, Overall Survival; DFS, Disease-Free Survival; PDAC, Pancreatic Ductal Adenocarcinoma; AR, Androgen Receptor; HRE, Hypoxia Response Element; miRNA, MicroRNA; SSB4, Saikosaponin B4; EGCG, Epigallocatechin Gallate; Sal A, Salvianolic Acid A; 4-AAQB, 4-Acetylantroquinonol B; PROTAC, Proteolysis-Targeting Chimera; SPR, Surface Plasmon Resonance; PDX, Patient-Derived Xenograft; ctDNA, Circulating Tumor DNA.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.