A dual-mechanism model of Selinexor in DLBCL: p53 reactivation and metabolic reprogramming

Abstract Background Diffuse large B-cell lymphoma (DLBCL) is an aggressive malignancy with limited therapeutic options in the relapsed or refractory setting. Selinexor, a selective inhibitor of nuclear export targeting XPO1, has demonstrated clinical activity in DLBCL. However, the molecular mechanisms underlying its antitumor effects remain incompletely defined. Methods We evaluated the clinical efficacy of Selinexor in a real-world cohort of lymphoma patients and performed integrative transcriptomic and proteomic analyses in DLBCL cell models representing germinal center B-cell–like (GCB) and non-GCB subtypes. Multi-omics profiling, pathway enrichment analysis, and targeted validation were used to characterize Selinexor-induced molecular alterations. Results Selinexor demonstrated meaningful clinical activity in DLBCL patients. Integrated multi-omics analyses revealed two principal mechanistic programs induced by XPO1 inhibition. First, Selinexor activated a p53-centered transcriptional network, characterized by suppression of key S-phase regulators, including GTSE1, PCNA, PCLAF, and CKS1B, leading to cell-cycle arrest and apoptosis. Second, Selinexor induced a metabolic stress response through downregulation of critical metabolic regulators such as SLC1A5 and RRM2, thereby restricting amino acid uptake and nucleotide biosynthesis. Notably, subtype-specific pathway coordination was observed: GCB models exhibited reciprocal regulation between p53 signaling and metabolic pathways, whereas non-GCB models displayed coordinated pathway activation. Conclusions These findings demonstrate that Selinexor exerts antitumor effects in DLBCL through concurrent activation of p53-mediated tumor suppression and disruption of metabolic homeostasis. The observed subtype-dependent pathway interactions provide mechanistic insight into Selinexor response and suggest potential opportunities for subtype-oriented therapeutic strategies. Trial registration Not applicable.