STIP1 signaling drives protein synthesis in pathological cardiomyocyte hypertrophy

Background: Stress-inducible phosphoprotein 1 (STIP1) is a co-chaperone involved in neuronal proteostasis and stress resilience. Although expressed in the heart, its role remains undefined. We assessed whether STIP1 deficiency impacts cardiac physiology and stress responses. Methods: STIP1 expression was analyzed in cardiac tissue from patients with heart failure. Haploinsufficient STIP1 mice (STIP1^+/-) received 7 days of isoproterenol (ISO) to induce cardiac injury, followed by proteomic, histological, and cardiomyocyte analyses. In vitro, neonatal rat cardiomyocytes (NRCMs) underwent STIP1 silencing and were evaluated using immunofluorescence, puromycin incorporation and western blotting. Results: STIP1 levels were reduced in cardiac tissue from heart failure patients, a pattern mirrored in STIP1^+/- mice. While STIP1^+/- hearts developed normally, ISO exposure led to increased inflammation and fibrosis compared with wild-type. Despite elevated injury markers, STIP1^+/- cardiomyocytes failed to undergo hypertrophy in response to ISO. Proteomic profiling identified impaired protein synthesis as the dominant signature in STIP1^+/-/ISO hearts, explaining the blunted hypertrophic response. To determine STIP1's role in cardiomyocyte hypertrophy and establish causality, we silenced STIP1 in NRCMs. Recapitulating in vivo findings, STIP1 silencing blocked ISO‑induced hypertrophy and similarly inhibited the hypertrophic responses to Ang II and phenylephrine in NRCMs. Consistent with proteomics, ISO failed to increase protein synthesis or eIF4E expression in STIP1-deficient NRCMs. Conclusion: STIP1 loss impairs the protein synthesis required for pathological cardiomyocyte hypertrophy, highlighting its essential role in cardiac adaptation to injury.