Gastric cancer is one of the highest mortality cancer types, and the leading cause of gastric cancer is persistent Helicobacter pylori infection. H. pylori secretes the enzyme HtrA, which cleaves adhesion proteins like E-cadherin and allows H. pylori to cross the epithelium. Recently, researchers used proteomics to find novel targets of HtrA associated with H. pylori. They confirmed E-cadherin as a target and identified human desmoglein-2 (hDsg2), neuropilin-1, ephrin-B2, and semaphorin-4D as potential targets. hDsg2 is a component of the desmosome junctions, which play important roles in epithelial cell-to-cell adhesion. Given the importance of cell-to-cell adhesion to epithelial health, the researchers focused on hDsg2. In vitro tests confirmed that HtrA secreted by H. pylori, and not other host cell proteases, cleaved hDsg2. This study is the first to demonstrate that HtrA secreted by H. pylori directly breaks down hDsg2 and suggests that HtrA is a ‘master key’ that allows H. pylori to penetrate the epithelium by breaking down adhesion proteins. More research is needed to unpack the full role of HtrA in H. pylori pathogenesis, but HtrA represents a promising future target to treat H. pylori infection.