Abstract In spite of recent advances in the field of undernutrition, current dietary therapy relying on the supply of high protein high calorie formulas is still plagued with transient recovery of impaired organs resulting in significant relapse of cases. This is partly attributed to the inadequacy of current research models in recapitulating clinical undernutrition for mechanistic exploration. Using 1636 Macaca fascicularis monkeys, a human‐relevant criterion for determining undernutrition weight‐for‐age z‐score (WAZ), with a cutoff point of ≤ −1.83 is established as the benchmark for identifying undernourished nonhuman primates (U‐NHPs). In U‐NHPs, pathological anomalies in multi‐organs are revealed. In particular, severe dysregulation of hepatic lipid metabolism characterized by impaired fatty acid oxidation due to mitochondria dysfunction, but unlikely peroxisome disorder, is identified as the anchor metabolic aberration in U‐NHPs. Mitochondria dysfunction is typified by reduced mito‐number, accumulated long‐chain fatty acids, and disruption of OXPHOS complexes. Soy peptide‐treated U‐NHPs increase in WAZ scores, in addition to attenuated mitochondria dysfunction and restored OXPHOS complex levels. Herein, innovative criteria for identifying U‐NHPs are developed, and unknown molecular mechanisms of undernutrition are revealed hitherto, and it is further proved that soypeptide supplementation reprogramed mitochondrial function to re‐establish lipid metabolism balance and mitigated undernutrition.
