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Background <p>Crotonylation, a recently identified lysine acylation, plays a critical role in post-translational modifications [<CitationRef CitationID="CR1">1</CitationRef>]. It has been implicated in tumorigenesis by modulating metabolic reprogramming [<CitationRef CitationID="CR2">2</CitationRef>], DNA repair, immune evasion [<CitationRef CitationID="CR3">3</CitationRef>], and oncogenic signaling pathways, including PKA-FAK-AKT and androgen receptor signaling [<CitationRef CitationID="CR4">4</CitationRef>]. The specific role of crotonylation in renal malignancy (RM) remains poorly understood, especially in interaction with gene expression and metabolic pathway interactions.</p> Methods <p>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.</p> Results <p>MR analysis demonstrated a significant association; increased expression of GCDH is likely to increase the risk of RM (OR = 1.25, <i>P</i> = 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, <i>P</i> = 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.</p> Conclusion <p>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.</p>

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Glutaryl-CoA dehydrogenase (GCDH) enhances renal malignancy risk via modulating glutarylcarnitine levels

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月10日

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  • Xuanshuo Liu,
  • Bohua Chen,
  • Jianghao Yuan,
  • Shuhao Li,
  • Lei Gao,
  • Mingyan Chu,
  • Shicang Fan,
  • Weiwei Fan

摘要

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.