Cell Rep. 2026 May 26;45(5):117215. doi: 10.1016/j.celrep.2026.117215. Epub 2026 Apr 28.

ABSTRACT

Early-stage lung adenocarcinoma (LUAD) in never smokers exhibits distinct biological features, yet the metabolic programs driving early invasion remain unclear. We integrate proteomic and lipidomic profiling of primary LUAD tumors from never smokers, matched normal adjacent tissues (NATs), and benign pulmonary nodules (BPNs). Integrated multi-omics analysis reveals coordinated dysregulation of lipid metabolism and immune signaling in early LUAD. Proteome-based network fusion stratifies invasive LUAD into immune-metabolic synergistic (IMS) and metabolic-stress-driven (MSD) subtypes. IMS tumors retain apolipoprotein-associated lipid modules and favorable immune features, whereas MSD tumors exhibit stress-response programs. Mechanistically, APOA1 and APOC1 emerge as key nodes linking lipid homeostasis to invasion, and their depletion promotes LUAD cell migration and invasion. We establish a two-protein, four-lipid diagnostic panel demonstrating robust performance across tissue and plasma cohorts. These findings provide a molecular basis for early detection and risk stratification in never smokers.

PMID:42054209 | DOI:10.1016/j.celrep.2026.117215

Dev Cell. 2026 Mar 12:S1534-5807(26)00079-1. doi: 10.1016/j.devcel.2026.02.014. Online ahead of print.

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.

PMID:41825439 | DOI:10.1016/j.devcel.2026.02.014

Dev Cell. 2026 Mar 12:S1534-5807(26)00079-1. doi: 10.1016/j.devcel.2026.02.014. Online ahead of print.

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.

PMID:41825439 | DOI:10.1016/j.devcel.2026.02.014