Causal relationship between cathepsins and esophageal adenocarcinoma: Mendelian randomization and single-cell RNA sequencing analysis

Abstract

Abstract The incidence of esophageal adenocarcinoma (EAC) has significantly increased, particularly in Western countries. Cathepsins are a group of lysosomal proteolytic enzymes; they are associated with the occurrence and progression of various tumors. However, the causal relationship between the cathepsin family and EAC remains unelucidated. To investigate this association, Mendelian randomization (MR) and bioinformatics analyses of single-cell RNA sequencing (scRNA-seq) data were performed. MR analyses revealed that high cathepsin B (CTSB) levels decreased EAC risk. Furthermore, scRNA-seq revealed that CTSB expression was primarily distributed in macrophages. In addition, MR analysis of CTSB and macrophage scavenger receptor types I and II verified their interrelationship; CTSB primarily affects the proinflammatory phenotype of macrophages. Our findings suggest that CTSB levels affect EAC progression by regulating the expression of macrophage scavenger receptor types I and II, which induce the proinflammatory phenotypes of macrophages. Therefore, targeting CTSB may provide avenues for EAC diagnosis and treatment.