Integrative multi-omics analysis reveals lipid/metabolite dysregulation and temporal decoupling in disease progression
TL;DR
Key metabolic control points (ceramide accumulation, arginine flux diversion, autophagy–lipid cross-talk, NAD⁺ salvage timing) were identified, highlighting potential targets for stage-specific therapeutic or nutritional interventions.
Abstract
Our study presents and applies a metabolomics-driven multi-omics integration strategy to elucidate dynamic pathway interactions during disease progression. We analyzed longitudinal metabolomics datasets from a Duchenne muscular dystrophy (DMD) mouse model (6–30 weeks) and an acute Bothrops asper envenomation model (1–24 h) to contrast chronic versus acute inflammation. In the DMD model, we predicted phased cross-talk between sphingolipid metabolism and neurotrophin signaling: an early proteomic surge followed by lipid-mediated amplification and a late convergence at the protein level. Arginine and proline metabolism exhibited early metabolite accumulation preceding delayed inferred protein changes, consistent with impaired nitric oxide synthesis and argininemia-like effect. We also predicted late-stage activation of the AGE–RAGE pathway in DMD, likely triggered by ceramide buildup, and an autophagy-related lipid metabolic shift at mid-stage. In the envenomation model, tryptophan–kynurenine and nicotinamide pathways for NAD⁺ biosynthesis were rapidly perturbed at the metabolite level (1–3 h) but induced corresponding predicted enzymes only by 24 h. Thyroid hormone signaling showed an early coupling of substrate availability (tyrosine surge at 1 h) with predicted stress-response proteins and a second, delayed wave of inferred transcriptional regulators at 24 h. Acute envenomation also triggered immediate glycine/serine utilization possibly for antioxidant defense and glycerophospholipid breakdown (via phospholipase A₂), whereas chronic DMD showed sustained glycine/serine engagement and inferred, unresolved phospholipid perturbation without protein-level compensation, which may result from chronic oxidative stress. Overall, our integrative analysis revealed time-specific, multi-layer molecular perturbations distinguishing acute toxin injury from chronic muscle degeneration. Key metabolic control points (ceramide accumulation, arginine flux diversion, autophagy–lipid cross-talk, NAD⁺ salvage timing) were identified, highlighting potential targets for stage-specific therapeutic or nutritional interventions.