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

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 NUFIP1-mediated ribophagy alleviates CD4(+) T lymphocyte PANoptosis in sepsis via the cGAS-STING pathway, highlighting the therapeutic potential of targeting ribophagy and PANoptosis pathways to mitigate immune paralysis and improve the outcomes following septic insults.