Given TRIM21 is not feasible as a therapeutic target for cardiac hypertrophy, due to its widespread expression in multi-organs, the cardiomyocyte-specific USP28-TRIM21 axis may avoid the potential and systemic side-effects induced by targeting TRIM21 alone, suggesting that targeting USP28 is a more specific strategy for cardiac hypertrophy therapy. The gene discussed is USP28; the disease is cardiac hypertrophy.