UCLA

The adult mammalian heart possesses a minimal capacity for regeneration, with cardiomyocyte turnover estimated at no more than ~1% per year1-3. Repeated insults—ranging from ischemic injury to metabolic stress—can precipitate cardiomyocyte dysfunction and death, ultimately culminating in heart failure. This progressive syndrome represents a major public health burden, currently affecting approximately 6.7 million individuals aged 20 years and older in the United States4. Alarmingly, its prevalence is projected to exceed 8 million by 2030, with associated healthcare costs soaring to $69.8 billion, reflecting a 127% increase in less than two decades4. Once established, symptomatic advanced heart failure carries a grim prognosis, with one-year survival rates as low as 10–20%4. A deeper mechanistic understanding of intrinsic cardioprotective pathways is essential to elucidate the molecular underpinnings of heart failure.Injured myocardium, when unable to undergo successful repair, is replaced by non-contractile fibrotic scar tissue due to the limited regenerative capacity of adult human cardiomyocytes5. While numerous strategies for cardiac repair and regeneration have demonstrated promise in preclinical studies, their clinical translation remains challenging. Cell-based therapies employing various stem cell types enhance cardiac function through paracrine effect, yet their therapeutic efficacy has been hindered by poor engraftment, limited survival, and potential pro-arrhythmogenic effects6. In parallel, cell-free approaches leveraging endogenous repair mechanisms—such as growth factors, modified RNAs, and extracellular vesicles—represent a compelling alternative but require further optimization of delivery methods and long-term efficacy evaluation7. In this context, our group recently identified insulin-like growth factor binding protein 3 (Igfbp-3) as a novel endogenous mediator of cardiac repair8. Igfbp-3 is the most abundant IGFBP in circulation and plays a pivotal role in regulating insulin-like growth factor (IGF) signaling by binding IGF-1 with high affinity9. Beyond its canonical IGF-dependent functions, Igfbp-3 is implicated in a variety of IGF-independent mechanisms, including nuclear signaling, DNA damage response, and cell stress adaptation10. In the context of cardiovascular biology, transgenic mice expressing human Igfbp-3 exhibit diffuse organomegaly, including cardiomegaly11. Furthermore, Igfbp-3 was recently identified as a key factor in interleukin-33 (IL-33)-mediated cardioprotection, where its expression was required to maintain autophagic flux in diabetic cardiomyopathy12. By adopting transcriptomic network analysis, we previously demonstrated that Igfbp-3 deficiency leads to the accumulation of detyrosinated microtubules—an indicator of increased cardiomyocyte stiffness and cardiomyopathy—in human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes, resulting in impaired contractile function8. Here, we uncover a previously unrecognized function of Igfbp-3 in regulating proteostasis through its interaction with Bag-3, a co-chaperone that directs misfolded proteins to the aggresome for degradation13. Loss-of-function mutations in Bag-3 are strongly associated with dilated cardiomyopathy, and reduced Bag-3 expression in human heart failure correlates with impaired contractile function14. Our findings demonstrate that Igfbp-3 directly interacts with Bag-3 to facilitate the clearance of misfolded proteins. To investigate the consequences of Igfbp-3 deficiency in the heart, we developed a tamoxifen-inducible, cardiomyocyte-specific Igfbp-3 knockout (Igfbp-3Δ/Δ) mouse model and employed the anthracycline doxorubicin (Dox) as a cardiac injury model15, allowing us to determine the molecular mechanism underlying the role of Igfbp-3 in maintaining protein homeostasis in the adult heart, under basal and streee conditions. Notably, the loss of Igfbp-3 exacerbated doxorubicin-induced proteostasis failure, leading to a markedly accelerated decline in systolic function and persistent diastolic dysfunction. This deterioration was accompanied by a significant accumulation of insoluble sarcomeric proteins and detyrosinated microtubules and an increase in myocardial stiffness. To assess the clinical relevance of our findings, we analyzed UK Biobank data, revealing that lower circulating Igfbp-3 levels were significantly associated with increased risk of heart failure and all-cause mortality, independent of traditional cardiovascular risk factors. Genetic analyses further supported a causal link, as carriers of rare Igfbp-3 loss-of-function and predicted pathogenic missense variants exhibited a 50% to nearly threefold higher risk of heart failure and all-cause mortality. These findings position Igfbp-3 as a critical regulator of Bag-3-mediated protein quality control, protecting cardiomyocytes from proteotoxic stress and preserving cardiac function under physiological and pathological conditions, with clinical data further linking low Igfbp-3 levels and rare Igfbp-3 variants to increased heart failure and mortality risk.