<scp>E3</scp> Ubiquitin Ligase <scp>TRIM21</scp> Exacerbates Pathological Cardiac Hypertrophy Through ASK1 K63‐Linked Polyubiquitination

Pathological cardiac hypertrophy is a major risk factor for myocardial ischemia, heart failure, and sudden cardiac death, yet its underlying mechanisms remain incompletely understood. Here, we identify Tripartite Motif Containing 21 (TRIM21) as a novel driver of pathological cardiac hypertrophy. TRIM21 was significantly upregulated in mouse hearts following transverse aortic constriction (TAC) and in neonatal rat cardiomyocytes stimulated with phenylephrine (PE). In vitro, TRIM21 knockdown attenuated PE-induced cardiomyocyte hypertrophy, whereas TRIM21 overexpression exacerbated this effect. Consistently, in vivo studies revealed that cardiomyocyte-specific TRIM21 overexpression in mice aggravated TAC-induced pathological cardiac hypertrophy. Mechanistically, TRIM21 directly interacted with and promoted K63-linked polyubiquitination of apoptosis signal-regulating kinase 1 (ASK1) at lysine 1064, leading to its enhanced phosphorylation and the subsequent activation of downstream c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (MAPK) pathways signaling. Crucially, the pro-hypertrophic effects of TRIM21 were abrogated by pharmacological inhibition of ASK1 (GS-4997). In conclusion, these findings define a novel TRIM21-ASK1 axis that drives pathological cardiac hypertrophy, highlighting TRIM21 as a promising therapeutic target for hypertrophic heart disease and heart failure.