LncRNA IRENA promotes peripheral T-cell lymphoma progression through scaffolding ARHGEF1 and FMNL1 to modulate RHOA GTPase/MAPK signaling.

Peripheral T-cell lymphoma (PTCL) is a highly heterogeneous group of lymphomas, characterized by aggressive behavior and poor outcomes. Investigating the key regulatory long non-coding RNAs (lncRNAs) is helpful to refine current prognostic models and identify novel therapeutic targets in PTCL. Using clinical and transcriptomic data from 172 patients (training cohort) and 36 patients (validation cohort) with newly diagnosed nodal PTCL, this study identified LINC01727 (also known as IRENA) as an independent prognostic marker associated with poor outcomes. Functional assays demonstrated that IRENA significantly promoted tumor growth and inhibited T-lymphoma cell apoptosis, underscoring its oncogenic role in PTCL. Mechanistically, cytoplasmic IRENA acted as a scaffold, enhancing the interactions between Rho guanine nucleotide exchange factor 1 (ARHGEF1) and Formin-like protein 1 (FMNL1), as well as their binding to RHOA. Multi-omics analysis revealed that the scaffolding activity of IRENA established a positive feedback loop, thereby provoking RHOA/MAPK activation. In the murine cell-derived xenograft model, targeting IRENA with an antisense oligonucleotide (ASO) effectively suppressed T-lymphoma growth. This study identifies IRENA as an independent prognostic biomarker for nodal PTCL patients, revealing its role in the self-organizing activation of RHOA GTPase. Targeting the IRENA/RHOA/MAPK signaling axis by ASO may represent a potential therapeutic strategy for PTCL.