Abstract

Unexplored biological 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) in human tissue specimens 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. The 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 cyclin-dependent kinase 2 (CDK2)-dependent cell-cycle regulation, thereby facilitating tumor proliferation in cellular and animal models. Together, these findings suggest that RIPK1-98 serves 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.