Albumin peptides alleviate dexamethasone-triggered malnutrition via arachidonic acid-mediated PPARα signaling in mice

Drug-induced malnutrition resulting from long-term glucocorticoid therapy has increasingly become a clinical concern. Dietary-derived active peptides represent an effective nutritional intervention strategy, yet the specific mechanisms of action of albumin peptides (AP) remain unclear. This study systematically evaluated the therapeutic effects of AP in a Dexamethasone (DEX)-induced malnutrition mouse model and elucidated its mechanisms through integrated analyses of liver transcriptomics, non-targeted metabolomics, and quantitative fatty acid profiling. Results demonstrated that AP administration ameliorated DEX-induced protein catabolism, increased serum prealbumin (PAB) levels by 183.66%, elevated total protein (TP) levels by 14.6%, and significantly reversed hepatic steatosis and gastrocnemius muscle degeneration. Transcriptomic analysis revealed that peroxisome proliferator-activated receptor alpha (PPARα) was the primary signaling pathway affected by AP, with gene expression levels of Ppara and related genes restored to normal ranges. Non-targeted metabolomic analyses further identified correlations between this transcriptional response and prostaglandin, leukotriene, and diacylglycerol levels. Fatty acid quantification showed that AP restored hepatic arachidonic acid levels by 17.3%. Correlation analyses revealed a significant positive relationship between hepatic arachidonic acid levels and PPARα expression (R≥0.97), reinforcing the hypothesis that arachidonic acid serves as a key endogenous ligand mediating the interaction between AP and PPARα. Additionally, AP restored short-chain fatty acid concentrations in feces, indicating the pivotal role of the gut-liver axis in phenotypic development. Together, these findings suggest that AP alleviates DEX-induced malnutrition partly through restoration of hepatic arachidonic acid metabolism and reactivation of PPARα signaling, supporting its potential as a functional food ingredient for drug-induced malnutrition.