Abstract Body: Cancer cachexia is a highly debilitating clinical syndrome of involuntary body mass loss featuring profound muscle wasting and leading to high mortality. Notably, cardiac wasting is prominent in cancer patients and cancer survivors. Cachexia studies present significant challenges due to the absence of human models and only short-term animal studies. To address this gap, we have developed a robust cachexia model characterized by marked cardiac muscle wasting with decreased cardiac muscle size and increased expression of protein degradation markers. Using human iPSC-derived cardiac muscle, we thoroughly evaluated morphological, functional, and metabolic alterations in the key stages of cachexia and the post-cachexia phase. C26 and HCT116 tumor cell lines were used to induce cachexia by two methods, pulse addition of cancer cell conditioned media or transwell-adapted co-culture. Cachectic cardiac myocytes exhibited reduced contraction amplitude, prolonged relaxation time, and increased oxygen consumption rate (OCR), as assessed by video-based and Seahorse analyses. Mechanistic studies revealed elevated Atrogin1 expression and increased LC3BII/LC3BI ratios, indicating increased ubiquitination activity and autophagy flux in cachectic cardiac muscle. Additionally, we examined the impact of increased Atrogin1 on the cardiac proteome by analyzing calcineurin A levels. Cachectic cardiac myocytes showed decreased calcineurin A protein levels, potentially affecting downstream targets. Interestingly, we discovered that NFAT, which characteristically translocate to the nucleus upon stimulation, was predominantly retained in the cytoplasm in cachectic cardiac muscle, a process critical for limiting transcriptional activity. In the post-cachexia phase following removal of conditioned media or cancer cells, Atrogin-1 and LC3BII/LC3BI levels normalized. In contrast, elevated OCR and reduced contractile function did not fully recover, suggesting that prolonged effects of altered metabolism warrant further study. In conclusion, this human-based model provides a valuable platform suitable for short and long-term studies of human heart muscle, offering critical insights into cancer-associated cardiac dysfunction and aiding in the development of potential therapies for cancer survivors.