Multi‐Organ DIA Proteomics Reveals a Shared Xenobiotic Metabolism Stress Program in a Patient‐Derived Xenograft Model

Cancer cachexia is a devastating systemic syndrome characterized by progressive body weight loss and multi-organ dysfunction, yet the proteome-level mechanisms driving synchronized organ remodeling remain incompletely defined. Here, we applied large-scale data-independent acquisition (DIA) proteomics to a reproducible xenograft model using cachexia-inducing human neuroendocrine carcinoma cells (AkuNEC). Compared with non-implanted controls, AkuNEC-bearing mice developed severe wasting of the heart, liver, kidney, and skeletal muscle. Quantitative profiling revealed extensive multi-organ proteome remodeling, with xenobiotic metabolism emerging as a recurrently altered program across all tissues. This shared "chemical stress" signature was overlaid with distinct organ-specific alterations. The liver, heart, and kidney exhibited convergent suppression of mTORC1 signaling, with the liver displaying additional complex reprogramming involving interferon responses and fatty acid metabolism. In contrast, skeletal muscle showed unique stress features, with coagulation emerging as the most prominent signature alongside xenobiotic metabolism. These findings establish a comprehensive multi-organ proteomic framework for cachexia, identifying systemic remodeling of xenobiotic and endobiotic stress pathways as a unifying pathophysiological feature. This pan-organ alteration implies a fundamental compromise in the host's capacity to detoxify endobiotics and therapeutics, providing a molecular rationale for the unpredictable pharmacokinetics and heightened drug toxicity frequently complicating cachexia management.