Authors
Lang Chen, Wenyi Lin, Lang Jiang, Xuehui Gao, Chenyan Yu, Jili Han, Zhenping Liu, Xuefeng Li, Mei He, Chang Li, Qilan Li, Chaoying Song, Jiqian Xu, You Shang
Published in
Advanced science (Weinheim, Baden-Wurttemberg, Germany). Pages e77366. Aug 24, 2026. Epub Aug 24, 2026.
Abstract
Patients with sepsis exhibit circadian disruption and persistent immunosuppression. However, the molecular mechanisms linking them remain unclear. Integration of multi-cohort transcriptomic and single-cell datasets shows that circadian gene dysregulation in patients with sepsis and septic mice correlates with disease severity and immunosuppressive states, with monocytes/macrophages emerging as a principal affected population. Sustained endotoxin stimulation elevates the core clock repressor NR1D1 in macrophages, which occupies the Igf2bp2 promoter and suppresses its transcription. Loss of IGF2BP2 destabilizes the V-ATPase subunit transcripts Atp6v1b2 and Atp6v0c through an m6A-dependent mechanism, disrupting phagolysosomal acidification rhythms and pathogen clearance. siRNA-mediated NR1D1 knockdown restores IGF2BP2 expression, circadian oscillations, and phagolysosomal function during the development of endotoxin tolerance. To achieve therapeutic delivery, we engineer hybrid membrane nanovesicles (siNR1D1@HM-LNP) that reverse circadian and immune dysregulation in septic mice, enhance bacterial clearance, and markedly improve survival. These findings establish an NR1D1-mediated circadian-immune coupling mechanism and provide a therapeutic strategy for targeting sepsis-induced immunosuppression.
PMID:
42636084
Bibliographic data and abstract were imported from PubMed on 25 Aug 2026.
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