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

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

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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