In mice with sepsis‑induced brain injury, giving the mitochondrial peptide MOTS‑c before the insult boosted survival, lowered sickness scores, reduced brain inflammation, and helped keep the blood‑brain barrier tighter, suggesting it protects the brain during severe infection.

Sepsis-associated encephalopathy (SAE) is a serious complication of sepsis, increasing short-term and long-term mortality. It involves neuroinflammation, neuronal damage, and blood-brain barrier (BBB) disruption. MOTS-c, a mitochondrion-derived peptide, exerts neuroprotective effects by modulating inflammatory responses and cellular functions. This study explored the protective effects of MOTS-c against brain injury in mice with LPS-induced sepsis. A mouse model of sepsis was established <i>via</i> intraperitoneal injection of LPS. The mice were divided into four groups: Control, Control&#x2009;+&#x2009;MOTS-c, LPS, and LPS&#x2009;+&#x2009;MOTS-c groups. The mice in the latter two groups received MOTS-c (20&#x2009;mg/kg) four hours before model establishment. Survival rates and the murine sepsis score (MSS) were recorded. H&amp;E staining, ELISA, Evans blue staining, brain water content detremination, immunofluorescence staining, western blotting, and qPCR were performed to assess brain tissue damage, inflammation, BBB permeability, and BBB-related protein expression. MOTS-c treatment increased the survival rate, decreased the MSS score, alleviated brain tissue damage, downregulated the expression of inflammatory factors, reversed the increase in BBB permeability, upregulated the expression of BBB-related proteins and CD31/PDGFR&#x3b2;, decreased the expression of GFAP/Iba-1/MMP-9, and increased the expression of neurotrophic factors in septic mice. MOTS-c effectively reduced mortality rates and the MSS, attenuated neuroinflammatory responses, mitigated increase in BBB permeability, promoted neurotrophic factor production, and protecting against brain injury in mice with LPS-induced sepsis.