Elucidating cancer cachexia-mediated aberrant cardiac wasting signaling in human iPSC-derived cardiac muscle

These changes were accompanied by significant FOXO1/3 activation, as demonstrated by reduced phospho/total FOXO ratios and nuclear translocation of FOXO1, promoting downstream atrophic remodeling. Interrogation of the Atrogin-1/Calcineurin A/NFAT axis identified this pathway as a central mediator of cachexia-induced cardiac atrophy. Cachectic cardiac myocytes exhibited significant upregulation of Atrogin-1, leading to a marked decrease in Calcineurin A protein levels.

This, in turn, impaired nuclear translocation of NFAT, thereby suppressing its transcriptional activity and downstream cell growth signaling. These molecular changes were accompanied by increased autophagic flux, as indicated by elevated LC3BII/LC3BI ratios. The convergent suppression of anabolic and activation of catabolic pathways produced substantial cardiac atrophy.

Following withdrawal of cachexia-inducing stimuli, Atrogin-1 and autophagy markers normalized within one week; however, contractile and metabolic impairments persisted, indicating delayed functional recovery. Collectively, these findings establish the FOXO/Atrogin-1/Calcineurin A/NFAT axis, operating within the broader context of AKT-mTORC1 suppression, as a central regulatory mechanism of cachexia-induced cardiac wasting and identify this pathway as a tractable therapeutic target.