Updated project metadata. Investigating the functions of the proteins with no or less functional annotations is an important goal of C-HPP (Chromosome-centric Human Proteome Project). In this study, we investigated the function of such a protein, ZSWIM1 (C20orf162). Its expression is upregulated in lung adenocarcinoma compared with the adjacent normal tissues and negatively correlated with the overall survival (OS). Overexpressing ZSWIM1 markedly promotes the proliferation, migration, invasion as well as epithelial-mesenchymal transition (EMT) in lung adenocarcinoma cells, while knocking down ZSWIM1 functions oppositely. Immunoprecipitation-mass spectrometry (IP-MS) identified the interactome of ZSWIM1 and we verified the interaction of it with the top partner, STK38. ZSWIM1 antagonized the function of STK38. Mechanically, ZSWIM1 promoted the activation of MEKK2/ERK1/2 pathway through interacting with STK38, leading to the release of MEKK2. Taken together, ZSWIM1 can be annotated as an oncogene in lung adenocarcinoma, and the STK38/MEKK2/ERK1/2 axis mediates its promoting role on lung adenocarcinoma.