Human Milk–Derived Peptide MAMP‐1 Ameliorates Sepsis‐Associated Acute Lung Injury in Mice Through APOA4 and the TLR4/NF‐κB Signaling Pathway

ABSTRACT Sepsis‐associated acute lung injury (SALI) significantly jeopardizes the health and survival prospects of neonates. Although breast milk has been identified to decrease the incidence and mortality rates associated with sepsis, the specific protective components remain unclear. In our research, milk‐derived antimicrobial peptide‐1 (MAMP‐1) is found to be significantly expressed and possessing favorable physicochemical properties within the breast milk for premature infants. In the experiment of MAMP‐1 acting on lipopolysaccharide (LPS)‐induced SALI in neonatal mice, MAMP‐1 pretreatment significantly increased survival rates, attenuated lung tissue damage, and reduced pro‐inflammatory cytokine levels in serum and lung tissue in LPS‐challenged mice. Transcriptome analysis further revealed that MAMP‐1 pretreatment inhibits the regulation of toll‐like receptor 4 (TLR4) signaling pathway, upregulates lipid metabolism related genes, especially apolipoprotein A‐IV (APOA4). This results in a reduced expression of key pro‐inflammatory factors and cholesterol levels, while simultaneously increasing high‐density lipoprotein cholesterol levels, thereby suppressing the dysregulated inflammatory response. These findings identify MAMP‐1 as a promising breast milk‐derived peptide for the prevention of neonatal SALI.