CircRNA-Encoded RIPK1-98 Protein Drives Lung Adenocarcinoma Progression

Biological unexplored matter—including uncharacterized genetic elements, molecular entities, and microbial components—remains poorly understood. Here, we use integrated multi-omics approaches to identify and characterize previously unrecognized protein products encoded by circular RNAs (circRNAs) and to delineate their roles in the progression of lung adenocarcinoma (LUAD). The transcription of precursor mRNA by RNA Polymerase Ⅱ subunit A (RPB1) is crucial for the biogenesis of these potential circRNA-encoded proteins. Functional and translational analyses link their expression to distinct pathological stages of LUAD in patients. A novel protein, RIPK1-98, encoded by circRIPK1, was identified as functionally distinct from its parental gene product, receptor interacting serine/threonine kinase 1 (RIPK1). RIPK1-98 modulates CDK2-dependent cell cycle regulation, thereby facilitating tumor proliferation in cellular and animal models. Together, these findings suggest that RIPK1-98 may serve as a biomarker for cell cycle progression in LUAD and highlight its potential as a therapeutic target to counteract resistance to first-line treatments, such as osimertinib.