In a mouse study, a modified version of the mitochondrial peptide humanin (humanin‑G) helped protect lungs after severe blood loss. It reduced tissue damage and improved blood pressure, but its ability to lower immune cell buildup in the lungs depended on a specific protein (AMPKα1). The findings suggest humanin can boost certain protective pathways, though it’s still early‑stage and only tested in animals.

<b>Background/Objectives</b>: The severity of acute lung injury is significantly impacted by age and sex in patients with hemorrhagic shock. AMP-activated protein kinase (AMPK) is a crucial regulator of energy metabolism but its activity declines with aging. Humanin is a mitochondrial peptide that exerts cytoprotective effects in response to oxidative stressors and is associated with longevity. Using a mouse model of hemorrhagic shock that mimics the clinical condition of adult patients, we investigated whether treatment with a humanin analog, humanin-G, mitigates lung injury and whether its mechanisms of action are dependent on the catalytic AMPK&#x3b1;1 subunit activation. <b>Methods</b>: Male and female AMPK&#x3b1;1 wild-type (WT) and knock-out (KO) mice (8-13 months old) were subjected to hemorrhagic shock by blood withdrawal, followed by resuscitation with shed blood and lactated Ringer's solution. The mice were treated with PEGylated humanin-G or vehicle and euthanized 3 h post-resuscitation. <b>Results</b>: Sex- and genotype-related differences were observed after hemorrhagic shock as lung neutrophil infiltration was more pronounced in the male AMPK&#x3b1;1 WT mice than the female WT mice; also, the male AMPK&#x3b1;1 KO mice experienced a significant decline in mean arterial blood pressure when compared to the male WT mice after resuscitation. The scores of histological lung injury were similarly elevated in all the male and female AMPK&#x3b1;1 WT and KO mice when compared to the control mice. At molecular analysis, acute lung injury was associated with the downregulation of AMPK&#x3b1;1/&#x3b1;2 catalytic subunits in the WT mice, whereas an increased activation of the signal transducer and activator of transcription-3 (STAT3) was observed in all the vehicle-treated groups. The in vivo administration of humanin-G ameliorated histological lung damage in all the groups of animals and ameliorated mean arterial blood pressure in the male AMPK&#x3b1;1 KO mice. The in vivo administration of humanin-G lowered lung neutrophil infiltration in the male and female AMPK&#x3b1;1 WT mice only but not in the KO mice. The beneficial results of humanin-G correlated with the lung cytosolic and nuclear activation of AMPK&#x3b1; in the male and female AMPK&#x3b1;1 WT groups, whereas STAT3 activation was not modified. <b>Conclusions</b>: In adult age, hemorrhage-induced acute lung injury manifests with sex-dependent characteristics. Humanin-G has therapeutic potential and the AMPK&#x3b1;1subunit is an important requisite for its inhibitory effects on lung leucosequestration, but not for the amelioration of lung alveolar structure or the hemodynamic effects of the peptide.