Work

lncRNA SNHG29-RPS-CYLD axis is mitochondrially localized and mediates apoptosis in rituximab-resistant DLBCL

Year: 2026

Type: article

Abstract: Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive non-Hodgkin lymphoma (NHL), and some cases are resistant to first-line rituximab (RTX) treatment, leading to poor prognosis. Our previous research found that phosphorylated cylindromatosis (CYLD) is a target regulating apoptosis in RTX-resistant DLBCL. Given the emerging role of lncRNA in apoptosis regulation, and the fact that CYLD-related lncRNA reversing drug resistance in various solid malignancies, this study aims to explore whether lncRNA can regulate phosphorylated CYLD to promote apoptosis in RTX-resistant DLBCL and the molecular mechanisms. RTX-resistant DLBCL models were generated via dose escalation. Mitochondrial dysfunction was assessed by ROS flux. Integrated multi-omics analyses combining RNA sequencing (Ribonucleic acid sequencing, STAR v2.7.10a, https://www.encodeproject.org/data-standards/rna-seq/long-rnas/ ) with computational and biochemical approaches identified CYLD as an apoptotic hub and SNHG29 as a resistance mediator. Mechanistic studies employed mitochondrial subfractionation, Co-IP, and lentiviral perturbation. Preclinical validation used xenograft mice models and clinical specimens, supported by assay for transposase-accessible chromatin with high throughput ATAC-Seq (Assay for Transposase-Accessible Chromatin using Sequencing, Bowtie2 v2.2.9, https://www.encodeproject.org/experiments/ENCSR637XSC/ ), ChIP-qPCR, and Bayesian network modeling. Through this research, we identified that high expression of phosphorylated CYLD is involved in the tumorigenesis and progression of DLBCL and serves as the core regulatory mechanism for DLBCL resistance to RTX. SNHG29 is an lncRNA associated with DLBCL resistance to RTX treatment. SNHG29 collaborates with CYLD through ribosomal proteins (RPS), and down-regulation of SNHG29 can down-regulate phosphorylated CYLD on the mitochondria, promoting apoptosis in RTX-resistant DLBCL. Nuclear transcription factor κB (NF-κB) is involved in this SNHG29 -RPS-CYLD axis regulation mechanism. This study reveals the molecular mechanism by which the SNHG29 -RPS-CYLD axis regulates apoptosis in rituximab-resistant (RTX-resistant) DLBCL at the mitochondria, thereby providing a novel target for drug development.

Source: Scientific Reports

DOI: 10.1038/s41598-026-75877-3