Causal role of phenylalanine and cholesterol metabolism in bladder cancer Chemoresistance: Insights from mendelian randomization and targeted molecular docking.

Bladder cancer (BLCA) exhibits profound chemoresistance, partly mediated by metabolic dysregulation. This study investigated the roles of phenylalanine (Phe) and cholesterol metabolism in BLCA chemoresistance using integrated omics and computational modeling. Transcriptomic analysis of the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets revealed that elevated hexokinase 2 (HK2) and low-density lipoprotein receptor (LDLR) expression correlates with poor response to cisplatin. Mechanistically, Phe catabolism via phenylalanine hydroxylase (PAH) activated mTORC1 signaling, promoting glycolysis and drug efflux, while cholesterol biosynthesis driven by SREBP2 enhanced ABCG2 transporter activity. Mendelian randomization (MR) analyses confirmed causal associations between Phe/cholesterol metabolism and chemoresistance risk. Pharmacological inhibition of HMG-CoA reductase or dietary phenylalanine restriction sensitized BLCA cells to cisplatin both in vitro and in xenograft models. Overexpression of FOLH1 or F7 reversed the inhibitory effects of Phe or cholesterol targeting, respectively, confirming their functional roles in resistance. These findings identify FOLH1 and F7 as mediators of metabolic resistance in BLCA and suggest metabolic targeting as a promising therapeutic strategy. However, whether combined inhibition of Phe and cholesterol pathways provides synergistic benefits over monotherapy remains to be determined in future studies.