Our findings highlight a protective role of USP20 by targeting STAT3 in hypertrophic models induced by TAC and Ang II, in contrast to USP28, which has been reported to exacerbate pathological cardiac hypertrophy in similar settings through mechanisms such as TRIM21‐mediated ROS accumulation.[50] This apparent contradiction underscores the complexity of DUB function in cardiovascular diseases and suggests that substrate specificity may play a pivotal role in determining their effects on downstream signaling pathways. This evidence concerns the gene TRIM21 and cardiac hypertrophy.