In summary, this work addressed the important scientific question of whether the murine ~42‐kDa ECSIT is encoded by the transcript variant Ecsit‐X4, and highlights its critical role in suppressing pressure overload‐induced pathological cardiac hypertrophy and mitigating mitochondrial dysfunction through a novel pathway involving interaction with STAT3 to enhance its activity. Here, ECSIT is linked to cardiac hypertrophy.