Dynamic monitoring and multi-pathway regulation of FBXO21 in renal clear cell carcinoma: from static marker to perspective of precision therapy

Dear Editor,

I read with great interest the study by Yang et al. which has made important advances in the field of clear cell renal carcinoma (ccRCC) and provides new perspectives on the diagnosis and treatment of ccRCC [1]. I would like to express my own sincere admiration and congratulations to the team for their achievements. On this basis, I would like to express some additional views on some key issues in this study, with a view to further promoting discussion and research in this field.

First, the excessive or single-minded focus on static FBXO21 expression in the current study is perhaps seriously detached from clinical reality. The study concluded that FBXO21 is a novel prognostic biomarker for ccRCC patients, and only listed that its high expression is associated with longer survival, but clinical decision-making should be immediate and responsive, serving the whole treatment process at all times. For example, a decrease or increase in the level of the marker during treatment should be in line with the clinical need for dynamic changes in the predictor. In fact, on this basis, it would be more meaningful to conduct a further retrospective analysis using existing data (including tumor tissue and blood samples before and after surgery) to initially assess the correlation between the expression level of FBXO21 and the response to treatment and prognosis by comparing the expression level of FBXO21 before and after treatment.

Furthermore, ccRCC is a highly heterogeneous tumor and different tumor cell subpopulations may respond differently to the expression and effects of FBXO21, and focusing only on the overall expression level may mask this heterogeneity. Different subpopulations of cacner-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) have different spatial localizations, which are differentially associated with patient prognosis and treatment response [2]. In addition, the heterogeneity of tumor cell subpopulations may also affect immune cell infiltration and function [3]. Future studies should utilize single-cell sequencing technology to analyze tumor cells from ccRCC patients at the single-cell level to reveal the differences in FBXO21 expression in different tumor cell subpopulations and its relationship with tumor heterogeneity. Spatial transcriptomics technology can also be combined to analyze the spatial distribution characteristics of FBXO21 in tumor tissues, so as to more comprehensively understand its mechanism of action in ccRCC.

Finally, studies have proposed the CREB pathway as a possible downstream mechanism of FBXO21, but additional studies have also confirmed that the PI3K/AKT/mTOR pathway is also a potential mechanism that deserves in-depth investigation. In ccRCC, activation of the PI3K/AKT/mTOR pathway is associated with tumor aggressiveness, drug resistance and poor prognosis [4]. Metastasis and proliferation of tumor cells are inhibited by regulating key proteins in the pathway. Future studies may consider using PI3K/AKT/mTOR pathway blockers (e.g., LY294002, NVP-BEZ235, etc.) to observe the effect of FBXO21 on the activity of key proteins in the pathway. The effects of FBXO21 overexpression or knockdown on the phosphorylation levels of PI3K, AKT and mTOR were examined by techniques such as Western blot. Similarly, the effect of FBXO21 on the activity of key molecules in the CREB pathway can be observed using CREB pathway blockers such as KG-5. By inhibiting the CREB pathway, more detailed evidence on the pathway is obtained. Considering the synergistic roles of the PI3K/AKT/mTOR pathway and the CREB pathway in tumorigenesis and progression, future studies could explore therapeutic strategies combining PI3K/AKT/mTOR pathway blockers and CREB pathway blockers. This combination therapy may be more effective in inhibiting tumor cell proliferation and metastasis and improving the therapeutic effect [5].