Background <p>Ribosomal protein L22 like 1 (RPL22L1) plays an important role in some tumours. However, its role in lung adenocarcinoma (LUAD) is less studied. This study aimed to analyse the molecular mechanism of RPL22L1 in LUAD and to identify new targets for LUAD treatment.</p> Methods <p>Real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) and Western blot (WB) were employed to detect the mRNA and protein expression, respectively. The CCK8 assay, colony formation assay, and transwell migration and invasion assay were utilized to assess the effects of RPL22L1 on LUAD cell proliferation, migration, and invasion. A nude mouse subcutaneous graft tumor model was used to evaluate the effect of RPL22L1 on the proliferative capacity of LUAD cells in vivo. Dual fluorescent reporter gene assays, ubiquitination immunoprecipitation assays, and protein degradation assays were conducted to explore the potential mechanism of RPL22L1 in LUAD.</p> Results <p>The study demonstrated that RPL22L1 could promote the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of LUAD cells. Mechanistically, the upregulation of RPL22L1 in LUAD activated the MAPK/ERK/Myc signaling pathway, which subsequently promoted the proliferation, migration, invasion, and EMT of LUAD cells. Furthermore, RPL22L1 was found to influence the ubiquitination of Myc protein, inhibit its degradation, and maintain its stability. Additionally, Myc protein could directly bind to the promoter region (-653 to -664) of RPL22L1 and enhance its transcriptional expression, forming a positive feedback loop to promote the developmental process of LUAD.</p> Conclusions <p>Our study revealed a positive feedback loop between RPL22L1 and Myc that drove LUAD progression.</p>