Exosomal microRNAs as Central Regulators of Cancer Cachexia: Multi-Omics Insights into Muscle Wasting and Adipose Browning

Cancer cachexia is a multifactorial syndrome marked by involuntary weight loss, skeletal muscle wasting, adipose tissue remodeling, and systemic metabolic dysfunction. Exosome-derived microRNAs (miRNAs) have emerged as key mediators, reprogramming host tissues and driving these hallmarks. However, no integrated framework has linked exosomal miRNAs to the proteomic and metabolomic alterations that characterize cachexia. This review critically synthesizes evidence on exosomal miRNAs in muscle atrophy, adipose browning, and systemic metabolic disruption. Tumor-secreted exosomal miRNAs activate proteolytic pathways (miR-21/29a via TLR7/8NF-κB/JNK), suppress antiapoptotic signals (miR-195<i>a</i>/125b targeting BCL-2), induce ER stress (miR-181a-3p), impair mitochondrial quality control (miR-122), and remodel metabolic signaling (miR-155, miR-183-5p). These mechanisms converge to produce proteomic signatures of enhanced proteolysis, apoptosis, and lipolysis, alongside metabolomic shifts toward amino acid efflux, fatty acid mobilization, and glycolytic inefficiency. This is the first integrated review linking exosomal miRNAs with proteomic and metabolomic signatures of cancer cachexia, offering a multiomics framework for biomarker discovery and therapeutic targeting. We highlight their potential as early biomarkers, therapeutic targets, and modulators of rehabilitation response, while outlining research gaps including limited clinical validation, intertumor heterogeneity, and the need for multiomics integration to advance translation into patient care.