Abstract
BACKGROUND: Crotonylation, a recently identified lysine acylation, plays a critical role in post-translational modifications [1]. It has been implicated in tumorigenesis by modulating metabolic reprogramming [2], DNA repair, immune evasion [3], and oncogenic signaling pathways, including PKA-FAK-AKT and androgen receptor signaling [4]. The specific role of crotonylation in renal malignancy (RM) remains poorly understood, especially in interaction with gene expression and metabolic pathway interactions. METHODS: This study integrates genome-wide association study (GWAS) summary statistics for RM from the FinnGen database, data on crotonylation-associated gene expression obtained from the eQTLGen consortium, and metabolite GWAS data obtained from the GWAS Catalog. A combined two-sample Mendelian randomization (MR), summary data-based Mendelian randomization (SMR), and mediation analyses were performed to investigate the causal link between Glutaryl-CoA dehydrogenase (GCDH) and RM, with a specific focus on glutarylcarnitine metabolism. RESULTS: MR analysis demonstrated a significant association; increased expression of GCDH is likely to increase the risk of RM (OR = 1.25, P = 0.0045). Mediation analysis revealed that elevated GCDH expression significantly reduced glutarylcarnitine (C5-DC) levels, which in turn was inversely associated with RM risk. A three-step MR-based mediation confirmed a significant mediating effect of glutarylcarnitine (β₁₂ = 0.0680, P = 0.002), with 30.25% of the total effect attributable to it. The robustness of these findings was further demonstrated by sensitivity analyses and SMR results. CONCLUSION: This study represents the first evidence that GCDH might exert an indirect pro-RM effect via the downregulation of glutarylcarnitine, thus providing new insights into tumor metabolic pathways and positioning glutarylcarnitine as a potentially diagnostic biomarker and therapeutic target for RM.