NUFIP1-Mediated Ribophagy Alleviates PANoptosis of CD4 + T Lymphocytes in Sepsis via the cGAS-STING Pathway

作者：Pengyue Zhao, Jingyan Li, Pengyi He, Yao Wu, Liyu Zheng, Xingpeng Yang, Jiaqi Yang, Ze Fu, Yun Xia, Ning Chen, Ning Dong, Zhiwen Luo, Ren-qi Yao, Xiaohui Du, Yong-ming Yao · 发表于：Research · 年份：2025 · DOI：10.34133/research.0895 · 被引用次数：10 · 研究领域：interferon and immune responses、Viral Infections and Vectors、Mosquito-borne diseases and control

T lymphocyte dysfunction represents a pivotal determinant of immunosuppression in sepsis. Our previous studies demonstrated that nuclear fragile X mental retardation-interacting protein 1 (NUFIP1)-mediated ribophagy conferred cytoprotection against apoptosis in CD4 + T lymphocytes during sepsis, thereby preserving host immunocompetence. Despite growing evidence linking PANoptosis to the pathogenesis of various diseases, the potential role of ribophagy in modulating CD4 + T lymphocytes’ PANoptosis in sepsis remains largely unclear. In the present study, we employed both lipopolysaccharide-stimulated Jurkat T cells and cecal ligation and puncture (CLP)-induced sepsis models to demonstrate marked exacerbation of CD4 + T lymphocyte PANoptosis following NUFIP1 knockdown (KD), associated with impaired immune function, as evidenced by diminished cytokine production and T cell proliferation. Tandem mass tagging (TMT) proteomic analysis identified Z-nucleic acid binding protein 1 (ZBP1)-mediated PANoptosome formation and the cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS-STING) pathway as critical nodes in ribophagy-dependent cytoprotection. Mechanistically, sepsis-induced ribosome collision activated the cGAS-STING signaling axis, which in turn recruited NUFIP1 to STING protein complexes. Clinical analysis of septic patients revealed enhanced ribophagy and PANoptosis in peripheral blood CD4 + T cells, consistent with the experimental findings. These results suggest that...