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bioRxiv · 10.1101/2025.10.16.682758

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

Yan, Q.·Guo, L.·Sun, Q.
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Abstract

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 I{kappa}B, suppressing NF{kappa}B 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.

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Yan, Q., Guo, L., Sun, Q.. 2025-10-16. The Janus face of Selinexor (KPT-330) in bacterial infection: short-term protection versus long-term lethality. https://doi.org/10.1101/2025.10.16.682758

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