TRIM40 Drives Pathological Cardiac Hypertrophy and Heart Failure via Ubiquitination of PKN2

ABSTRACT Pathological cardiac hypertrophy is a major predisposing factor for heart failure (HF). This study investigates the role of the E3 ubiquitin ligase Tripartite Motif‐Containing 40 (TRIM40) in cardiac hypertrophy. Using TRIM40 knockout (TRIM40 ^−/− ), cardiac‐specific knockdown and overexpressing mice, pathological hypertrophy was induced by angiotensin II (Ang II) infusion or transverse aortic constriction (TAC). Results showed that TRIM40 expression was upregulated in hypertrophic hearts. TRIM40 deficiency attenuated cardiac hypertrophy and dysfunction, whereas its overexpression exacerbated pathological remodeling. Mechanistically, TRIM40 binds PKN2 via its B‐box domain and, in a manner requiring its C29‐dependent E3 ligase activity, promotes K63‐linked ubiquitination of PKN2. This leads to enhanced PKN2 phosphorylation at Ser815 and activation of downstream signaling. Pharmacological inhibition of PKN2 attenuated cardiac remodeling induced by TRIM40 overexpression. These findings reveal that TRIM40 drives cardiac hypertrophy through K63‐linked ubiquitination and activation of PKN2, identifying TRIM40 as a promising candidate for therapeutic intervention in HF.