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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Pharmacology of Anti-Cancer Drugs
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1443045
This article is part of the Research Topic Genomic Discoveries and Pharmaceutical Development in Urologic Tumors View all 13 articles

Pharmacological targets of SGLT2 inhibition on prostate cancer mediated by circulating metabolites: A drug-target Mendelian randomization study

Provisionally accepted
Yilong Lin Yilong Lin 1Yue Zhang Yue Zhang 2Songsong Wang Songsong Wang 1Lin Cao Lin Cao 3Ruidan Zhao Ruidan Zhao 1Xilai Ma Xilai Ma 1Qiaolu Yang Qiaolu Yang 1Liyi Zhang Liyi Zhang 1*Qingmo Yang Qingmo Yang 4*
  • 1 Xiamen University, Xiamen, Fujian Province, China
  • 2 Xiangya Hospital, Central South University, Changsha, Hunan Province, China
  • 3 Guangdong Medical University, Zhanjiang, Guangdong, China
  • 4 Xiamen Cancer Center, First Affiliated Hospital of Xiamen University, Xiamen, China

The final, formatted version of the article will be published soon.

    The relationship between sodium-glucose cotransporter 2 (SGLT2) inhibitors and prostate cancer is still unknown. Although these inhibitors can influence tumor glycolysis, the underlying mechanism requires further exploration.A two-sample two-step MR was used to determine 1) causal effects of SGLT2 inhibition on prostate cancer; 2) causal effects of 1400 circulating metabolites or metabolite ratios on prostate cancer; and 3) mediation effects of these circulating metabolites. Genetic proxies for SGLT2 inhibition were identified as variants in the SLC5A2 gene and glycated hemoglobin level (HbA1c). Additionally, positive control analysis on type 2 diabetes mellitus (T2DM) was conducted to test the selection of genetic proxies. Phenome Wide Association Study (PheWAS) and MR-PheWAS analysis were used to explore potential treatable diseases and adverse outcomes of SGLT2 inhibitors.Genetically predicted SGLT2 inhibition (per 1 SD decrement in HbA1c) was associated with reduced risk of T2DM (odds ratio [OR] = 0.66 [95% CI 0.53, 0.82], P = 1.57×10 -4 ); prostate cancer (0.34 [0.23, 0.49], P = 2.21×10 -8 ) and prostate-specific antigen (0.26 [0.08, 0.81], P = 2.07×10 -2 ). The effect of SGLT2 inhibition on prostate cancer was mediated by uridine level, with a mediated proportion of 9.34% of the total effect. In MR-PheWAS, 65 traits were found to be associated with SLGT2 inhibitors (P < 1.78×10 -5 ) , and among them, 13 were related to diabetes.Our study suggested that SGLT2 inhibition could lower prostate cancer risk through uridine mediation. More mechanistic and clinical research is necessary to explore how uridine mediates the link between SGLT2 inhibition and prostate cancer.

    Keywords: SGLT2 inhibitor, prostate cancer, Uridine, Mendelian randomization, PheWAS

    Received: 03 Jun 2024; Accepted: 19 Jul 2024.

    Copyright: © 2024 Lin, Zhang, Wang, Cao, Zhao, Ma, Yang, Zhang and Yang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Liyi Zhang, Xiamen University, Xiamen, 361005, Fujian Province, China
    Qingmo Yang, Xiamen Cancer Center, First Affiliated Hospital of Xiamen University, Xiamen, China

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