Background
Sepsis, a critical condition characterized by life-threatening organ dysfunction, arises from a dysregulated host response to infection. The resultant immunosuppression constitutes the primary mortality factor in critically ill patients during the advanced stages of sepsis. Within this context, the compromised function of CD4⁺ T lymphocytes, pivotal effectors of the adaptive immune response, significantly contributes to the immunosuppressive milieu of sepsis. While programmed cell death represents a fundamental host defense mechanism, recent investigations reveal the simultaneous activation of pyroptosis, apoptosis, and necroptosis, culminating in a novel cell death paradigm termed PANoptosis. This discovery offers a new framework for elucidating the pathophysiological underpinnings of diverse diseases. Nevertheless, the precise role and regulatory mechanisms governing PANoptosis within T lymphocytes during sepsis remain elusive.

Research Progress
Professors Yao Yongming and Du Xiaohui, leading a research group at the Chinese PLA General Hospital, have published groundbreaking findings demonstrating that CD4⁺ T lymphocytes undergo PANoptosis during sepsis. Their study identifies ribophagy, a cellular self-degradation process, as a crucial protective mechanism. The research elucidates that ribosomal collision in CD4⁺ T cells during sepsis potently activates the cGAS-STING innate immune pathway. Through advanced techniques including proteomics, gene deletion, and small molecule inhibition, the team established that NUFIP1, a key receptor protein for ribophagy, directly interacts with STING. This NUFIP1-mediated ribophagy effectively clears aberrant ribosomes, thereby suppressing ZBP1-driven PANoptosome formation and mitigating CD4⁺ T lymphocyte PANoptosis. This novel mechanistic insight carries substantial biological implications: selective NUFIP1 gene deletion in CD4⁺ T cells of murine sepsis models exacerbated immune deficiency, intensified multi-organ injury, and markedly decreased survival. Conversely, intervention with the STING-specific inhibitor SN-011 ameliorated these detrimental outcomes and significantly improved survival rates. Notably, the researchers observed the activation of ribosome autophagy and PANoptosis in peripheral blood CD4⁺ T lymphocytes of human septic patients, underscoring the significant clinical translational potential of this discovery.

Future Prospects
This research comprehensively elucidated the pathogenesis and regulatory pathways governing CD4⁺ T cell PANoptosis during sepsis. Professors Yao and Du’s team demonstrated that NUFIP1-mediated ribophagy confers cellular protection via the cGAS-STING signaling cascade. These findings significantly advance our comprehension of the pathological and physiological underpinnings of sepsis and offer novel therapeutic avenues for addressing immune dysregulation.

The complete study is accessible via DOI: 10.34133/research.0895