• Tuo Peng, Tian Li, and Caihua Zhang.
• Department of Urology, People's Hospital Affiliated to Chongqing Three Gorges Medical College, 27 Guoben Rd, Chongqing 404100, China.
• Postgrad Med J. 2025 Jan 16.

BackgroundPrevious studies have established a relationship between cathepsins and renal cancer. Nonetheless, the specific causal connection between the two factors continues to be ambiguous. The aim of this study is to evaluate the causal relationship between cathepsins and renal cancer via employing Mendelian randomization (MR).MethodsThe summary data of genome-wide association study were used for univariable MR (UVMR), reverse MR, and multivariable MR (MVMR) analyses. The primary MR method used in this study was Inverse variance weighting.ResultsUVMR analysis showed that cathepsin Z increased the overall risk of renal cancer and cathepsin F were observed increased the risk of clear cell renal cell carcinoma. Furthermore, the concentration of cathepsin S had a significant positive correlation with the risk of papillary renal cell carcinoma (pRCC), whereas that of cathepsin G was negatively correlated with the risk of pRCC. Reverse MR analysis showed that renal cancer reduced the concentration of cathepsin H. MVMR analysis showed that the concentration of cathepsin B had a significant positive correlation with overall risk of renal cancer and pRCC. In addition, a higher concentration of cathepsin S was significantly associated with an increased risk of pRCC.ConclusionThis study confirmed a direct link between cathepsins and the risk of renal cancer. Specifically, cathepsin S has a significant positive correlation with the risk of pRCC. The findings of our research could provide significant contributions to both fundamental and clinical investigations pertaining to renal cancer. Key message What is already known on this topic? - Previous studies have suggested the role of some cathepsins in renal cancer occurrence and progression. However, the causal link between different cathepsins and renal cancer is unknown. What this study adds? - Our Mendelian randomization (MR) study revealed that the effects of different cathepsins on the risk of renal cancer. Remarkably, both univariable MR and multivariable MR demonstrated that the levels of cathepsin S increases the risk of papillary renal cell carcinoma. How this study might affect research, practice or policy? - The findings offer novel insights into the relationship between cathepsins and renal cancer, which may have implications for the prevention and management of renal cancer.© The Author(s) 2025. Published by Oxford University Press on behalf of Fellowship of Postgraduate Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

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