Causal relationship between cathepsins and esophageal adenocarcinoma remains unresolved

Determine whether members of the lysosomal protease cathepsin family (including but not limited to cathepsin B, E, F, G, H, L2, O, S, and Z) have a causal effect on the risk of esophageal adenocarcinoma, and characterize the direction of any such effects to inform potential diagnostic and therapeutic strategies.

Background

The paper investigates whether specific cathepsins are causally linked to esophageal adenocarcinoma (EAC) and Barrett's esophagus (BE) using Mendelian randomization (MR), TWAS, scRNA-seq, and sc-eQTL analyses. Prior literature reported dysregulated cathepsin activity in EAC/BE tissues, but prospective and causal evidence was limited. The authors motivate their paper by noting that the causal relationship between the cathepsin family and EAC had not been established.

This open problem frames the need to move beyond observational associations to causal inference for individual cathepsins in EAC pathogenesis. Although the paper reports a negative causal association for cathepsin B (CTSB) with EAC/BE risk, it does not comprehensively resolve causality for the entire cathepsin family, leaving the broader question open.