Work

Transient protein phosphorylation promotes disease tolerance to sepsis

Year: 2026

Type: preprint

Abstract: SUMMARY One of the enduring paradoxes of sepsis is that organs fail despite little evidence of irreversible tissue injury. Emerging evidence suggests that this state reflects a regulated metabolic shutdown within host tissues, yet whether such hypometabolism contributes to pathology or promotes survival remains unclear. This phenomenon resembles torpor, a physiological state of profound hypometabolism induced by environmental stress and mediated through reversible protein phosphorylation. Septic hypometabolism is identified here as a conserved tissue-specific metabolic adaptation which is characterized by transient activation of Glycogen Synthase Kinase (GSK)3β. This activation reduced disease severity of bacterial sepsis without affecting the hosts pathogen burden, indicating that GSK3β activity promotes disease tolerance to infection. Consistent with these findings, plasma signatures associated with GSK3β inhibition correlated with worse clinical outcomes in patients with sepsis. Together, these results define septic hypometabolism as a torpor-like response and identify reversible phosphorylation as a key mechanism governing host adaptation to severe bacterial infection.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.64898/2026.06.09.731055