Introduction:
Traditional longitudinal epidemiological investigations have demonstrated an association between appendectomy and the cumulative incidence of Colorectal cancer(CRC). However, there is a paucity of evidence for a causal linkage between Appendectomy and CRC from alternative methodologies.

Material and methods:
We extracted summary statistics for CRC, appendectomy, 1,400 metabolites, and 91 inflammatory proteins from the largest European ancestry genome-wide association studies (GWAS) and the FinnGen. Using two-sample bidirectional Mendelian randomization (MR), we explored the causal relationship between appendectomy and CRC. Moreover, we employed a two-step MR approach to identify metabolites and inflammatory proteins that mediatie the effects of appendectomy on CRC risk and analyzed their potential mediator variables. Furthermore, we utilized the significant single nucleotide polymorphisms (SNPs) associated with the risk of CRC due to appendectomy, searched for the nearest genes in the FinnGen, and explored the relationship between these genes and the prognosis of CRC patients by analyzing transcriptomic data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO).

Results:
Two-sample MR analysis revealed a significant causal effect of appendectomy on the increased risk of CRC. Two-step MR analysis identified carnitine and interleukin-13 (IL-13) as key mediators in the positive causal relationship between appendectomy and CRC. Survival analysis showed that the upregulation of HLX and OSR1 expression is positively correlated with poor prognosis in CRC patients.

Conclusions:
This MR investigation substantiates the causal impact of appendectomy on colorectal cancer, with carnitine and IL-13 acting as partial mediators of this effect.