Discovery, delineation, and therapeutic targeting of a hyper-translation pathway driving cytokine release syndrome.

Abstract

Cytokine release syndrome (CRS) is a potentially life-threatening inflammatory condition. However, the defining features that distinguish it from self-resolving inflammation remain poorly understood. In this study, we identified monocyte/macrophage hyper-translation as a hallmark of CRS pathogenesis in patient samples. To uncover the molecular drivers of this phenomenon, a CRISPR screen followed by genetic validation pinpointed BCAP as a critical regulator of hyper-translation. Mechanistically, BCAP activated the RSK-EIF4B axis, fueling hyperactive translation in macrophages. Genetic ablation of RSK attenuated CRS-associated inflammation, and pharmacological inhibition of RSK alleviated CRS symptoms in a humanized mouse model. These findings establish hyper-translation as a key pathogenic feature of CRS and highlight protein translation as a druggable pathway, opening venues for therapeutic interventions of CRS and other inflammatory diseases.