Letter to the Editor: Targeting the IGF2BP3/FBXO32/cGMP-PKG axis as a therapeutic modality for gastric cancer: A promising strategy

Abstract

Gastric cancer (GC) remains a significant health concern, highlighting the need for more precise and effective therapeutic strategies. We read with interest the study published in the World Journal of Gastroenterology by Si et al, which demonstrates that the N⁶-methyladenosine (m⁶A) reader IGF2BP3 promotes GC progression by binding to FBXO32 mRNA and activating the cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) pathway. This pioneering study establishes a link between IGF2BP3 overexpression and poor prognosis and confirms its role in regulating GC cell function and glucose metabolism. Notably, a selective PKG inhibitor suppresses GC cell proliferation, highlighting its therapeutic potential. The study enhances current understanding of m⁶A-mediated oncogenesis in GC, identifies the IGF2BP3/FBXO32/cGMP-PKG axis as a potential target for precision therapy, and lays the groundwork for future investigation. Subsequent studies should further examine the underlying mechanisms, tumor microenvironment interactions, and emphasize translational research to bridge basic science and clinical application.

Key Words: Gastric cancer; N⁶-methyladenosine; Cyclic guanosine monophosphate-protein kinase G; Molecular markers; IGF2BP3; FBXO32

Core Tip: Gastric cancer (GC) needs more precise therapies, and Si et al’s study presents promising insights by revealing that the N⁶-methyladenosine (m⁶A) reader IGF2BP3 drives GC progression through an m⁶A-dependent post-transcriptional mechanism. This fills the long-standing gap in understanding the downstream targets of IGF2BP3 in GC and, for the first time, links the IGF2BP3/FBXO32 axis to the cyclic guanosine monophosphate-protein kinase G pathway. Additionally, it promotes discussions on the role of m⁶A in tumorigenesis and points to critical directions such as mechanistic exploration, tumor microenvironment crosstalk and subtype-specific research, laying key groundwork for translating this axis into GC clinical treatment.

TO THE EDITOR

We read with great interest the recent article by Si et al[1] in the World Journal of Gastroenterology, which elucidates the oncogenic role of the N⁶-methyladenosine (m⁶A) reader IGF2BP3 in gastric cancer (GC) progression. This study addresses a critical gap in the understanding of m⁶A-mediated post-transcriptional regulation and proposes a novel therapeutic pathway for GC.

The m⁶A, a key RNA modification, plays a pivotal role in GC development. Evidence indicates that m⁶A levels in peripheral blood RNA of patients with GC are significantly elevated, increasing with disease progression and metastasis, and declining following surgical intervention. These findings suggest that m⁶A levels may serve as a superior noninvasive biomarker for GC diagnosis compared to traditional markers such as carcinoembryonic antigen and carbohydrate antigen 19-9[2]. The m⁶A modification contributes to GC pathogenesis through various enzymes and signaling pathways. For example, the m⁶A methyltransferase METTL3 has demonstrated notable oncogenic activity in GC. Studies have shown that METTL3 promotes SPHK2 translation via m⁶A modification, thereby enhancing GC cell proliferation, migration, and invasion by suppressing KLF2 expression[3]. METTL3 also enhances the stability of MYC mRNA via m⁶A modification, leading to increased translation and activation of the PI3K/AKT pathway, thereby promoting GC cell proliferation and inhibiting apoptosis[4]. In addition, METTL3 stabilizes YAP1 mRNA through m⁶A modification, activating the Hippo signaling pathway and facilitating GC cell proliferation[5]. Furthermore, METTL3 stabilizes ZMYM1 mRNA via m⁶A modification. ZMYM1, a transcriptional repressor, suppresses E-cadherin promoter activity by recruiting the CtBP/LSD1/CoREST complex, thereby inducing the EMT process and ultimately promoting GC metastasis[6].

The role of the m⁶A demethylase FTO in GC also warrants attention. FTO enhances the expression of Caveolin-1 and ITGB1 proteins through demethylation, promoting GC cell metastasis by regulating mitochondrial dynamics and the integrin signaling pathway, respectively[7,8]. FTO also activates the PI3K/AKT/mTOR pathway by demethylating HOXB13, thereby increasing GC cell proliferation and invasion[9]. Additionally, FTO stabilizes ULK1 mRNA through demethylation. ULK1, an autophagy-related protein, inhibits apoptosis in GC cells by activating the autophagy pathway[10].

The m⁶A modification also influences GC progression by regulating long non-coding RNAs (lncRNAs). The lncRNA LINC00958 exhibits increased stability through m⁶A modification and promotes aerobic glycolysis in GC cells by interacting with GLUT1 mRNA[11]. Moreover, lncRNA THAP7-AS1 aids nuclear entry of CUL4B under transcriptional activation of SP1 and m⁶A modification of METTL3, thereby activating the PI3K/AKT pathway and advancing GC progression[12].

The m⁶A modifications not only regulate cancer cell behavior but also correlate with immune cell infiltration patterns within the tumor microenvironment (TME). Elevated expression of the m⁶A reader YTHDF1 in GC tissues is associated with reduced infiltration of CD8⁺ T cells. YTHDF1 enhances the translation of USP14 mRNA by recognizing its m⁶A modification. USP14, a deubiquitinating enzyme, suppresses CD8⁺ T cell infiltration by inhibiting their activation[13]. Notably, inhibition of YTHDF1 significantly increases CD8⁺ T cell infiltration and enhances the therapeutic efficacy of anti-programmed death 1 (PD-1) monoclonal antibody treatment in a GC mouse model[13]. Furthermore, distinct m⁶A modification profiles are associated with specific tumor immunophenotypes, including immune rejection, immune inflammation, and immune desert types, highlighting the potential of m⁶A signatures to inform immunotherapy strategies[14].

Despite two limitations in the study by Si et al[1]—namely, limited source diversity of clinical samples and the lack of detailed elucidation of the molecular mechanisms underlying GC cell glucose metabolism—we believe the work makes a significant contribution to GC research in three key areas, summarized in Table 1. First, although the oncogenic role of the m⁶A reader IGF2BP3 has been established in other malignancies, its function in GC has remained incompletely understood. This study is the first to demonstrate that IGF2BP3 exerts protumor effects in GC via an m⁶A-dependent post-transcriptional regulatory mechanism, specifically by binding to the m⁶A site at position 1427 of FBXO32 mRNA. This interaction enhances FBXO32 protein expression without altering its transcriptional level, thereby addressing a critical gap in the understanding of how IGF2BP3 modulates downstream targets in GC. Notably, this mechanism differs from the previously reported roles of IGF2BP3 in other cancers and identifies FBXO32 as a critical m⁶A-mediated effector of IGF2BP3 in GC. Second, the study establishes the IGF2BP3/FBXO32/cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) axis as a central driver of GC progression. Both in vitro and in vivo assays demonstrate that IGF2BP3-induced upregulation of FBXO32 activates cGMP-PKG signaling, thereby promoting GC cell proliferation, migration, invasion, and glucose metabolism, while suppressing apoptosis. The PKG inhibitor KT5823 reverses these effects, validating the axis as a druggable target. This finding addresses a gap in understanding GC signaling biology, particularly as the role of the cGMP-PKG pathway has previously been implicated in cancers such as breast and colon cancer, but not in connection with IGF2BP3 or FBXO32[15]. Third, the study provides translational relevance. High IGF2BP3 expression correlates with unfavorable clinicopathological features and poor survival, establishing it as a prognostic biomarker. Targeting this axis presents a novel therapeutic strategy, bridging preclinical insights with clinical application in GC treatment.

Table 1 Key contributions of the study on IGF2BP3/FBXO32/cyclic guanosine monophosphate-protein kinase G axis in gastric cancer.

Contribution category	Core content	Innovation & significance
Mechanistic elucidation	First reveals IGF2BP3 promotes GC via m6A-dependent regulation: Binds FBXO32 mRNA to upregulate its protein (no transcriptional change)	Fills IGF2BP3 downstream gap in GC; unique mechanism; identifies FBXO32 as key m6A effector
Axis identification	Identifies IGF2BP3/FBXO32/cGMP-PKG as GC driver; KT5823 (PKG inhibitor) reverses its oncogenic effects	Links cGMP-PKG to IGF2BP3/FBXO32 (novel in GC); validates druggable target
Translational relevance	High IGF2BP3 = poor prognosis (prognostic biomarker); axis targeting offers new therapy	Bridges preclinical-clinical translation; aids prognosis/treatment

cGMP: Cyclic guanosine monophosphate; PKG: Protein kinase G; m⁶A: N⁶-methyladenosine; GC: Gastric cancer.

To further enhance the understanding of this mechanism and its translational relevance, we propose several points for additional discussion and exploration, as illustrated in Figure 1. Several mechanistic aspects of the IGF2BP3/FBXO32/cGMP-PKG axis in GC remain to be elucidated. First, the relationship between IGF2BP3 and glucose metabolism in GC cells requires further investigation. The authors observed changes in intracellular glucose, lactate, and ATP levels following modulation of IGF2BP3, suggesting a potential role in aerobic glycolysis, a hallmark of cancer metabolism[16]. While these findings are compelling, they would be strengthened by more comprehensive metabolic profiling, including measurements of oxygen consumption rate and extracellular acidification rate, to quantify oxidative phosphorylation and glycolytic flux. In addition, evaluating the expression and activity of glycolytic enzymes such as HK2 and LDHA, along with transporters such as GLUT1, would help determine whether IGF2BP3 regulates glycolysis directly or indirectly via the cGMP-PKG pathway. Moreover, investigating the role of FBXO32, an E3 ubiquitin ligase, in its interactions with glycolysis-related proteins—particularly in mediating the degradation of negative regulators of glycolysis—could reveal additional layers of metabolic regulation. Second, the study suggests a potential bidirectional regulatory relationship between IGF2BP3 and FBXO32, indicating that FBXO32 may inversely influence IGF2BP3 expression; however, the underlying molecular mechanism remains to be validated. For instance, could FBXO32 regulate IGF2BP3 stability through ubiquitination? Does FBXO32 target IGF2BP3 for proteasomal degradation, thereby establishing a feedback loop that fine-tunes the IGF2BP3/FBXO32/cGMP-PKG axis? Investigating this possibility would introduce an additional layer of complexity to the regulatory network and clarify whether IGF2BP3 functions not only as a regulator but also as an FBXO32 substrate. Finally, downstream effectors of the cGMP-PKG pathway beyond phospho-VASP remain to be identified. These effectors may include proteins involved in cell cycle progression, such as Cyclin D1, or molecules associated with migration, such as MMP9, thereby contributing to a more comprehensive understanding of how this pathway drives GC malignancy.

Figure 1 Future research roadmap for IGF2BP3/FBXO32/cyclic guanosine monophosphate-protein kinase G axis in gastric cancer. cGMP: Cyclic guanosine monophosphate; PKG: Protein kinase G; NGS: Next-generation sequencing; dPCR: Digital PCR; MSI: Microsatellite instability; TME: Tumor microenvironment; GC: Gastric cancer; OCR: Oxygen consumption rate; ECAR: Extracellular acidification rate; m⁶A: N⁶-methyladenosine; PD-L1: Programmed death ligand-1.

Although this study focuses on GC cells, the significant role of the TME in tumor progression and treatment resistance warrants further investigation. Future work should examine how the IGF2BP3/FBXO32 axis modulates TME components. In particular, it is crucial to determine whether IGF2BP3 overexpression in GC cells influences the polarization of tumor-associated macrophages toward a pro-tumor M2 phenotype or modulates the activation of cancer-associated fibroblasts to secrete pro-metastatic cytokines such as transforming growth factor-beta and interleukin-6. In addition, exploring crosstalk between the axis and immune checkpoints, including programmed death ligand-1 expression, could inform the development of combination immunotherapies, such as the use of anti-PD-1 antibodies in conjunction with PKG inhibitors. Finally, analyzing IGF2BP3/FBXO32 levels in circulating tumor cells or exosomes from GC patients may enable dynamic monitoring of treatment response and recurrence, addressing limitations of static tissue biopsies.

The clinical relevance of this study can be enhanced through targeted translational research. First, as the current analysis is based on GC tissue from a single institution, it is essential to validate the prognostic and diagnostic significance of the IGF2BP3/FBXO32 axis in multicenter studies with large, diverse patient cohorts. Future investigations should determine whether IGF2BP3 and FBXO32 expression, assessed by immunohistochemistry or liquid biopsy approaches, correlates with clinicopathological characteristics across heterogeneous populations, thereby supporting their utility as robust biomarkers. Second, it is critical to optimize therapeutic strategies that target this axis. The PKG inhibitor KT5823 exhibits antiproliferative effects; however, it may also exert off-target activities that contribute to drug resistance. The development of selective PKG inhibitors or small molecules that specifically disrupt the IGF2BP3-FBXO32 interaction—such as those that block IGF2BP3 binding to the m⁶A site in FBXO32 mRNA—could enhance therapeutic efficacy. Additionally, the potential to combine these targeted inhibitors with existing treatments, including chemotherapy, anti-HER2 agents, or m⁶A methyltransferase/demethylase inhibitors such as METTL3 inhibitors, warrants investigation to determine whether such combinations can synergistically suppress GC progression. Third, the authors employed subcutaneous xenograft models to validate the role of IGF2BP3 in GC growth, a commonly used experimental approach. Future studies should consider using patient-derived xenograft models, which better reflect the genetic heterogeneity and TME of clinical GC, to provide more reliable predictions of therapeutic efficacy in humans.

Moreover, although the cancer samples were pathologically confirmed as gastric adenocarcinoma or signet-ring cell carcinoma, the specific molecular subtypes of GC—such as anaphase-promoting complex (APC)- or p53-mutated populations, distinct sub-classes of APC-truncated mutants, or DNA repair-deficient variants—were not explicitly characterized. To enable subtype-specific targeted interventions, it is critical to identify core markers for each subtype. Targeted next-generation sequencing and digital PCR should be employed to detect APC and p53 mutations. Long-read sequencing, in combination with functional assays, may be used to differentiate among APC-truncated sub-classes. For the identification of DNA repair-deficient types, techniques such as microsatellite instability-PCR and immunohistochemistry can be applied. Ultimately, integrating multi-omics data with clinical parameters will facilitate the development of a diagnostic panel to guide personalized treatment strategies.

CONCLUSION

Precision medicine plays a critical role in the management of GC. The study by Si et al[1] represents a significant advancement in understanding the disease by proposing a promising strategy targeting the IGF2BP3/FBXO32/cGMP-PKG axis. Future investigations should aim to further elucidate the underlying mechanisms, explore interactions within the TME, and advance targeted translational research to effectively bridge foundational discoveries with clinical application.

ACKNOWLEDGEMENTS

We are genuinely thankful to Wei-Yu Ye for her support and encouragement.