Tumor-educated adipocytes promote muscle wasting via EV-packaged miR-221-3p targeting IRS1 in pancreatic cancer cachexia.

Pancreatic ductal adenocarcinoma (PDAC) is often burdened by cachexia, a metabolic disorder characterized by extensive and severe adipose tissue wasting and muscle atrophy that shortens life expectancy. While adipose depletion frequently coincides with myopathy, the precise molecular mediators by which remodeled adipocytes drive muscle atrophy remain largely undefined. Here, we delineated a pathogenic 'feed-forward' axis wherein tumor-derived inflammatory stimuli (IL-6/TNF-α) drove adipocytes to secrete extracellular vesicles (EVs) enriched with miR-221-3p. Genetic tracing confirmed that these EVs circulated systemically and were actively taken up by skeletal muscle. At the molecular level, EV-delivered miR-221-3p repressed IRS1, leading to the collapse of the PI3K-AKT survival cascade. Consequently, this inhibition triggered severe metabolic dysregulation by coupling impaired GLUT4-dependent glucose transport with heightened ubiquitin-proteasome activity, ultimately culminating in muscle atrophy. Silencing miR-221-3p via AAV-sponges or antagomirs conferred significant protection against muscle wasting and functional decline in cachectic mice. Importantly, high levels of circulating EV-miR-221-3p not only marked the presence of cachexia but were also significantly associated with reduced overall survival in PDAC patients. Collectively, our findings uncover a pathogenic adipose-to-muscle axis mediated by EV-miR-221-3p, offering a novel therapeutic target and a promising non-invasive biomarker for PDAC-associated cachexia.