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

  • Cell Rep Med. 2025 Dec 30:102531. doi: 10.1016/j.xcrm.2025.102531.
Xingxian Liu  1 ,  Jiaqi Li  1 ,  Yajing Zhang  2 ,  Yang Liu  3 ,  Chunmeng Wang  3 ,  Yao Wang  3 ,  Yunqi Liu  1 ,  Yuzhuo Yang  1 ,  Yao Su  4 ,  Youxue Lu  5 ,  Wenyan Wang  6 ,  Yang-Xin Fu  6 ,  Xin Lin  1 ,  Deng Pan  5 ,  Weidong Han  7 ,  Xiaoyu Hu  8
Affiliations
  • 1. Institute for Immunology, Tsinghua University, Beijing, China; School of Basic Medical Sciences, Tsinghua University, Beijing, China; Tsinghua-Peking Center for Life Sciences, Beijing, China.
  • 2. Department of Bio-therapeutic, the First Medical Center, Chinese PLA General Hospital, Beijing, China; Department of Myeloma and Lymphoma, Beijing GoBroad Boren Hospital, GoBroad Medical Institute of Hematology (Beijing Center), Beijing, China.
  • 3. Department of Bio-therapeutic, the First Medical Center, Chinese PLA General Hospital, Beijing, China.
  • 4. National Protein Science Facility, School of Life Science, Tsinghua University, Beijing, China.
  • 5. School of Basic Medical Sciences, Tsinghua University, Beijing, China; Tsinghua-Peking Center for Life Sciences, Beijing, China.
  • 6. School of Basic Medical Sciences, Tsinghua University, Beijing, China; State Key Laboratory of Molecular Oncology, Tsinghua University, Beijing, China.
  • 7. Department of Bio-therapeutic, the First Medical Center, Chinese PLA General Hospital, Beijing, China. Electronic address: [email protected].
  • 8. Westlake University School of Medicine, Hangzhou, China; Westlake University School of Medicine-affiliated Hangzhou First People's Hospital, Hangzhou, China. Electronic address: [email protected].
PMID: 41475340 DOI: 10.1016/j.xcrm.2025.102531
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.

Keywords
CAR T therapy; cytokine release syndrome; immunotherapy; inflammation; protein translation.
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