The Janus face of Selinexor (KPT-330) in bacterial infection: short-term protection versus long-term lethality

The clinical application of the anti-cancer drug KPT-330 (Selinexor) has been associated with increased infection-related mortality, yet its direct impact on infection pathogenesis remains unclear. Here, we found that KPT-330 treatment reduced host survival from 66% to 22% in a mouse model of bacterial pneumonia. Interestingly, KPT-330 conferred transient lung protection at 24 h post infection by blocking the nuclear export of IκB, suppressing NFκB signaling and immune cell recruitment. Meanwhile, KPT-330 induced apoptosis of lung epithelial cells, enhancing bacterial adhesions and invasion, and leading to dramatically increased bacterial load. These effects culminated in a compensatory immune rebound and more severe lung injury at later stages. Adjunctive therapy with the antibiotic polymyxin E (colistin) rescued survival, whereas the immunosuppressant dexamethasone did not, underscoring that timely bacterial clearance is critical for managing this adverse effect. Our findings provide direct evidence that KPT-330 exacerbates bacterial infection and advocate for an adjunctive antimicrobial prophylaxis strategy to ensure its safer use, especially in high-risk patients.