ITCH and cardiovascular disorder: Through bioinformatics analysis and experimental verification, ITCH was shown to be the downstream molecular target of miR-216a-5p, which acts as an E3 ubiquitin ligase31,33,60 and is widely involved in various cardiovascular diseases.61,62 The elevated miR-216a-5p in EXOs from adriamycin cardiomyopathy patients induced cardiotoxicity in hiPSC-CMs, consistent with previous reports linking miR-216a-5p to cardiac dysfunction.63 To validate the miR-216a-5p/ITCH axis in vivo while enhancing translational relevance, we established PDX models using patient-derived breast cancer tissues.