Background and Aims:Colorectal cancer(CRC)has a complex pathogenesis,and current treatments remain limited in efficacy for advanced metastatic disease.Dasatinib is a multi-target tyrosine kinase inhibitor that has shown potential antitumor activity in various solid tumors.This study aimed to evaluate the causal relationships between dasatinib-related target genes and CRC based on genetic variation,and to explore the mediating role of immune cells,thereby providing genetic epidemiological evidence for the prevention and targeted therapy of CRC.Methods:Dasatinib-related target genes were identified through DrugBank,and the corresponding eQTLs,GWAS data for CRC(ebi-a-GCST90018808),and 731 immune-cell traits were obtained from the IEU OpenGWAS database.A two-sample Mendelian randomization(MR)framework with a two-step mediation approach was applied:first,to assess the causal relationship between dasatinib target genes(as exposures)and CRC;second,to evaluate the causal effects between target genes and immune cells,as well as between immune cells and CRC;and finally,to calculate the proportion of mediated effects.Wald ratio,inverse-variance weighted(IVW),MR-Egger,MR-PRESSO,Cochran's Q,I2,and leave-one-out analyses were used to examine heterogeneity,horizontal pleiotropy,and robustness.Results:MR results showed that dasatinib-associated inhibition of ABL1 was significantly associated with a reduced risk of CRC(OR=0.511 0,95%CI=0.323 1-0.808 0,P=0.004 1).Inhibition of YES1 was also associated with decreased CRC risk(IVW OR=0.889 9,95%CI=0.811 6-0.975 8,P=0.013 1),with no evident heterogeneity or horizontal pleiotropy among the corresponding SNPs.Further analysis revealed that dasatinib-related inhibition of YES1 significantly reduced the levels of IgD-CD24-AC level(OR=0.818 0,95%CI=0.678 2-0.986 7,P=0.035 7),and this immune cell subset itself was identified as a risk factor for CRC(OR=1.105 7,95%CI=1.029 6-1.187 5,P=0.005 7).Mediation analysis indicated that IgD-CD24-AC accounted for-9.89%and 17.31%of the mediation effects in the ABL1→CRC and YES1→CRC pathways,respectively.Conclusion:Genetic evidence from MR suggests dasatinib-target genes ABL1 and YES1 are causally linked to reduced CRC risk,with IgD-CD24-AC partially mediating the YES1-related protective effect.These findings point to immune-mediated mechanisms underlying dasatinib's potential influence on CRC risk;further experimental validation and replication across populations are warranted.

Background and Aims:Colorectal cancer(CRC)has a complex pathogenesis,and current treatments remain limited in efficacy for advanced metastatic disease.Dasatinib is a multi-target tyrosine kinase inhibitor that has shown potential antitumor activity in various solid tumors.This study aimed to evaluate the causal relationships between dasatinib-related target genes and CRC based on genetic variation,and to explore the mediating role of immune cells,thereby providing genetic epidemiological evidence for the prevention and targeted therapy of CRC.Methods:Dasatinib-related target genes were identified through DrugBank,and the corresponding eQTLs,GWAS data for CRC(ebi-a-GCST90018808),and 731 immune-cell traits were obtained from the IEU OpenGWAS database.A two-sample Mendelian randomization(MR)framework with a two-step mediation approach was applied:first,to assess the causal relationship between dasatinib target genes(as exposures)and CRC;second,to evaluate the causal effects between target genes and immune cells,as well as between immune cells and CRC;and finally,to calculate the proportion of mediated effects.Wald ratio,inverse-variance weighted(IVW),MR-Egger,MR-PRESSO,Cochran's Q,I2,and leave-one-out analyses were used to examine heterogeneity,horizontal pleiotropy,and robustness.Results:MR results showed that dasatinib-associated inhibition of ABL1 was significantly associated with a reduced risk of CRC(OR=0.511 0,95%CI=0.323 1-0.808 0,P=0.004 1).Inhibition of YES1 was also associated with decreased CRC risk(IVW OR=0.889 9,95%CI=0.811 6-0.975 8,P=0.013 1),with no evident heterogeneity or horizontal pleiotropy among the corresponding SNPs.Further analysis revealed that dasatinib-related inhibition of YES1 significantly reduced the levels of IgD-CD24-AC level(OR=0.818 0,95%CI=0.678 2-0.986 7,P=0.035 7),and this immune cell subset itself was identified as a risk factor for CRC(OR=1.105 7,95%CI=1.029 6-1.187 5,P=0.005 7).Mediation analysis indicated that IgD-CD24-AC accounted for-9.89%and 17.31%of the mediation effects in the ABL1→CRC and YES1→CRC pathways,respectively.Conclusion:Genetic evidence from MR suggests dasatinib-target genes ABL1 and YES1 are causally linked to reduced CRC risk,with IgD-CD24-AC partially mediating the YES1-related protective effect.These findings point to immune-mediated mechanisms underlying dasatinib's potential influence on CRC risk;further experimental validation and replication across populations are warranted.