Unveiling the association between HMG-CoA reductase inhibitors and bladder cancer

This study utilized Mendelian randomization (MR) analysis and genome-wide association study (GWAS) data to investigate the association between commonly prescribed drugs and bladder cancer (BLCA) risk. Our results revealed that HMGCR inhibitors, specifically simvastatin, are significantly associated with a reduced BLCA risk. We further showed that simvastatin could significantly inhibit BLCA proliferation and epithelial-mesenchymal transition in animal models, with transcriptomic data identifying several associated pathways. Higher levels of HMGCR were linked with BLCA development and progression, and certain blood lipids, such as lipoprotein particles and VLDL cholesterol, might influence BLCA risk. These findings suggested that HMGCR inhibitors, particularly simvastatin, could be potential treatment options or adjuvant therapies for BLCA. Meanwhile, RhoB is a key protein involved in the regulation of bladder cancer cell metastasis by simvastatin. Therefore, we tested the changes of key genes in bladder cancer cells after simvastatin (HMGCR inhibitor) treatment and overexpression of RhoB, respectively, using RNA sequencing. To investigate the role of HMGCR and RhoB in BLCA, we treated the T24 BLCA cell line with 2 μM simvastatin for 48 hours. In addition, T24 cells were transfected with empty plasmid and RhoB overexpression plasmid for 48 hours. Then, in order to ensure the reliability of the results, we performed independent experiments three times for each sample. Finally, the 12 samples were analyzed by RNA sequencing. (O = DMSO, S = simvastatin, TN = empty vector, TR = RHOB overexpression).