Purpose: Cancer cachexia, characterized by persistent weight loss, skeletal muscle atrophy, and adipose tissue reduction-with progressive skeletal muscle wasting being the predominant manifestation-represents a major cause of mortality in pancreatic ductal adenocarcinoma (PDAC) patients. Cachexia is a common and severe complication in PDAC, significantly impacting patients' quality of life and prognosis. This study investigates the role of the mitochondrial calcium uniporter (MCU) in PDAC-associated cachexia, potentially offering novel interventional strategies for its prevention. Experimental Design: MCU expression was analyzed in PDAC patient tissues and correlated with cachexia incidence. Spontaneous tumor models and orthotopic PDAC models using MCU-overexpressing and control stable cell lines were established to evaluate tumor progression and muscle atrophy. Neutrophil extracellular traps (NETs) formation was detected by H3cit/MPO/DAPI multiplex immunofluorescence. NETs function was examined through anti-Ly6G-mediated neutrophil depletion, DNase I treatment, and Pad4⁻/⁻ mice. Secretome analysis identified MCU-regulated mechanisms in NETs formation, validated through recombinant protein treatment and receptor inhibition. The role of CCDC25 was investigated using genetic knockout models and AAV9-mediated skeletal muscle-specific silencing. Results: MCU overexpression significantly correlated with cachexia incidence and reduced skeletal muscle mass in PDAC patients. Compared to the MCU-overexpression group, control mice demonstrated attenuated tumor growth and preserved muscle mass independent of tumor burden. MCU-overexpressing PDAC models showed significantly elevated NETs infiltration in skeletal muscle, while NETs clearance prevented muscle atrophy. MCU overexpression induced cellular senescence and senescence-associated secretory phenotype (SASP) secretion (particularly C3 and CXCL1), promoting NETosis through C3aR and CXCR2 signaling. CCDC25 was identified as a critical NET DNA receptor in skeletal muscle, mediating muscle atrophy through RAC1-dependent ROS production. Conclusion: Our study reveals a novel signaling pathway wherein tumor MCU overexpression promotes cellular senescence and SASP secretion, driving NETs formation through C3/CXCL1 signaling. NETs engage CCDC25 receptors on muscle cells, activating the RAC1-ROS signaling pathway that ultimately leads to muscle atrophy. Impact: These findings establish the MCU-NETs-CCDC25 axis as a key mechanism in PDAC-associated cachexia and suggest multiple therapeutic strategies-including MCU inhibition, NETs degradation, and CCDC25 blockade-providing new directions for alleviating cachexia and preserving muscle mass in cancer patients.