Multi-Omics Reveals Dysregulation of the Endosome-Lysosome-Autophagy Axis and Immune-Inflammatory Imbalance in Elderly Sepsis

<h4>Background</h4>Elderly sepsis (ES), characterized by dual insults of aging and sepsis, is associated with substantial morbidity and mortality and exhibits distinct pathophysiological features. Elucidating these unique mechanisms is critical for developing precise therapeutic strategies and improving patient prognoses.<h4>Methods</h4>We performed integrative analyses of untargeted metabolomics and proteomics in four groups: young and elderly healthy controls and young and elderly patients with sepsis. Characteristic metabolites and proteins in ES were identified by using a three-step screening pipeline. Pairwise correlation analyses were conducted on the screened molecules; those with a ∣r_s∣ ≥ 0.4 were retained for subsequent KEGG and/or GO functional enrichment analyses.<h4>Results</h4>Two characteristic metabolites and seven proteins were identified: D-aspartic acid, LysoPC (18:1/0:0), SCGB3A2, ATP6V1E1, APOA1, AP1G1, INHBC, CRYZL1, and CXCL14. Enriched metabolic pathways comprised D-Amino acid metabolism, alanine, aspartate, and glutamate metabolism, and glycerophospholipid metabolism. Enriched protein-centric functional terms were linked to the endocytic vesicle lumen, proton-translocating V-type ATPase, receptor ligand activity, and signaling receptor activator activity, etc. Collectively, these findings highlight perturbations in the endosome-lysosome-autophagy axis and immune-inflammatory imbalance in ES.<h4>Conclusion</h4>This study established a hypothesis implicating dysregulation of the endosome-lysosome-autophagy axis and immune-inflammatory imbalance in ES, thus providing a theoretical foundation for further elucidating the pathophysiological mechanisms underlying ES and developing precise therapeutic interventions.