Combining Mendelian Randomization and Experimental Validation to Reveal the Causal Relationship Between Hallux Valgus...

Hallux valgus (HV) is a common foot deformity influenced by genetic, pathological, and traumatic factors, yet its relationship with serum metabolites (SMs) remains unclear. This study employed two-sample Mendelian randomization (SMR) to investigate causal associations between 1400 SMs and HV, identifying Cysteine and Glycochenodeoxycholate 3-sulfate as negatively correlated with HV occurrence, with no significant reverse causal effect from HV on their levels. Focusing on Cysteine, 548 target genes were predicted from four databases (DrugBank, SuperPred, Genecards, and SwissTargetPrediction) and 793 HV-related genes were retrieved from Genecards, yielding 47 overlapping genes. KEGG enrichment analysis revealed that these intersecting genes were involved in pathways such as cellular senescence and the AGE-RAGE signaling pathway in diabetic complications. Among them, fibroblast growth factor receptor 2 (FGFR2) showed a positive causal relationship with Cysteine and a negative causal relationship with HV, which was validated in patient samples showing significantly lower serum Cysteine levels and bone tissue FGFR2 expression in the HV group compared to non-HV controls (p < 0.001). Additionally, Isogranulatimide was identified as a marine-derived active compound targeting FGFR2, with molecular docking and dynamic simulations confirming favorable binding activity. These findings suggest that Cysteine may play a protective role in the development and progression of HV, with FGFR2 serving as a key mediating target that could reduce HV risk both indirectly through elevated Cysteine levels and directly through its own regulation, offering valuable reference for targeted diagnosis and therapy in clinical practice.