Selinexor as a multi-pathway regulator of the XPO1-inflammation Axis: Mechanisms, evidence in inflammatory diseases, and translational challenges.

Abstract

Selinexor (KPT-330), the first oral selective nuclear export inhibitor, simultaneously modulates key signaling pathways, including NF-κB, JAK/STAT, FOXO, Nrf2, and NLRP3, by blocking XPO1-mediated nuclear export, thereby offering a novel multi-target strategy for treating chronic inflammatory diseases. This review systematically integrates existing preclinical and early clinical evidence within the framework of "cytokine signaling networks", focusing on elucidating the molecular mechanisms and biological effects of selinexor in suppressing proinflammatory factor production, mitigating oxidative stress, and regulating inflammatory tissue-remodeling networks. Recent findings further indicate that SINE compounds can remodel proteostasis, including ankyrin repeat and SOCS box-containing protein 8 (ASB8)/Cullin-RING ligase 5 (CRL5)-associated XPO1 degradation and regulation of the ACE2-TMPRSS2-XPO1 coronavirus-entry network. However, current evidence primarily stems from in vitro and animal studies, and randomized controlled trials in human chronic inflammatory diseases are lacking. Moreover, hematopoietic and gastrointestinal toxicities observed in oncology settings suggest a narrow therapeutic window. This review emphasizes a stepwise translational logic from protein turnover and receptor regulation to next-generation XPO1 inhibitors. At present, selinexor is more suitable as a mechanistic tool for exploring the XPO1-inflammation axis, whereas inflammatory-disease translation will require eltanexor or related agents with more favorable tissue distribution and tolerability, together with precisely stratified clinical studies.

Key Findings

• Selinexor inhibits XPO1-mediated nuclear export, modulating multiple signaling pathways including NF-κB, JAK/STAT, FOXO, Nrf2, and NLRP3.
• Selinexor suppresses proinflammatory factor production, reduces oxidative stress, and regulates inflammatory tissue remodeling in preclinical models.
• Current evidence is mainly from in vitro and animal studies; clinical trials in human chronic inflammatory diseases are lacking, and toxicity limits its therapeutic window.

Clinical Significance

Citation

Zhang Hai, Liu Xinyi, Zhao Yunhuaet al.. Selinexor as a multi-pathway regulator of the XPO1-inflammation Axis: Mechanisms, evidence in inflammatory diseases, and translational challenges. International immunopharmacology. 2026-Jul-25.