Crosstalk between fibroblasts and cardiomyocytes (CMs) plays a critical role in cardiac remodelling during heart failure (HF); however, the underlying molecular mechanisms remain obscure. Recently, a secretory protein, Integrin beta-like 1 (ITGBL1) was revealed to have detrimental effects on several diseases, such as tumours, pulmonary fibrosis, and hepatic fibrosis; whereas the effect of ITGBL1 on HF is unclear. The purpose of this study was to evaluate its contribution to volume overload-induced remodelling. In this study, we identified ITGBL1 was highly expressed in varied heart diseases and validated in our TAC mice model, especially in fibroblasts. To investigate the role of ITGBL1 in in vitro cell experiments, neonatal rat fibroblasts (NRCFs) and cardiomyocytes (NRCMs) were performed for further study. We found that in comparison to NRCMs, NRCFs expressed high levels of ITGBL1. Meanwhile, ITGBL1 was upregulated in NRCFs, but not in NRCMs following angiotensin-II (AngII) or phenylephrine stimulation. Furthermore, ITGBL1 overexpression promoted NRCFs activation, whereas knockdown of ITGBL1 alleviated NRCFs activation under AngII treatment. Moreover, NRCFs-secreted ITGBL1 could induce NRCMs hypertrophy. Mechanically, ITGBL1-NME/NM23 nucleoside diphosphate kinase 1 (NME1)-TGF-β-Smad2/3 and Wnt signalling pathways were identified to mediate NRCFs activation and NRCMs hypertrophy, respectively. Finally, the knockdown of ITGBL1 in mice subjected to transverse aortic constriction (TAC) surgery recapitulated the in vitro findings, demonstrating blunted cardiac fibrosis, hypertrophy, and improved cardiac function. ITGBL1 is an important functional mediator between fibroblast–cardiomyocyte crosstalk and could be an effective target for cardiac remodelling in HF patients. Schematic diagram depicting the mechanism of ITGBL1-mediated cardiac hypertrophy and fibrosis. Pro-fibrotic stimulation leads to fibroblast activation and secretion of ITGBL1 from fibroblasts. In fibroblasts, ITGBL1 competitively binds NME1 and inhibits the interaction between STRAP and NME1, thereby activating the TGF-β-Smad2/3 pathway and further activating fibroblasts. In cardiomyocytes, ITGBL1 leads to cardiomyocyte hypertrophy through activation of the Wnt pathway. Finally, the combination of fibroblast activation and cardiomyocyte hypertrophy leads to the development of HF.

Abnormal cardiac fibrosis is the main pathological change of post-myocardial infarction (MI) heart failure. Although the E3 ubiquitin ligase FBXL8 is a key regulator in the cell cycle, cell proliferation, and inflammation, its role in post-MI ventricular fibrosis and heart failure remains unknown. FBXL8 was primarily expressed in cardiac fibroblasts (CFs) and remarkably decreased in CFs treated by TGFβ and heart subjected to MI. The echocardiography and histology data suggested that adeno-associated viruses (AAV9)-mediated FBXL8 overexpression had improved cardiac function and ameliorated post-MI cardiac fibrosis. In vitro, FBXL8 overexpression prevented TGFβ-induced proliferation, migration, contraction, and collagen secretion in CFs, while knockdown of FBXL8 demonstrated opposite effects. Mechanistically, FBXL8 interacted with Snail1 to promote Snail1 degradation through the ubiquitin–proteasome system and decreased the activation of RhoA. Moreover, the FBXL8ΔC3 binding domain was indispensable for Snail1 interaction and degradation. Ectopic Snail1 expression partly abolished the effects mediated by FBXL8 overexpression in CFs treated by TGFβ. These results characterized the role of FBXL8 in regulating the ubiquitin-mediated degradation of Snail1 and revealed the underlying molecular mechanism of how MI up-regulated the myofibroblasts differentiation-inducer Snail1 and suggested that FBXL8 may be a potential curative target for improving post-MI cardiac function.

Pathological cardiac hypertrophy, driven by mitochondrial dysfunction and maladaptive remodeling, remains a therapeutic challenge. This study explores the cardioprotective properties of tectorigenin (Tec) in the context of transverse aortic constriction (TAC)-induced hypertrophy, focusing on mitochondrial homeostasis. In animal models, administration of Tec improved survival rates, reduced cardiac dysfunction, and decreased hypertrophy and fibrosis in TAC mice, while preserving mitochondrial function. In in vitro experiments, Tec was found to inhibit the enlargement of cardiomyocytes and mitochondrial impairment induced by phenylephrine. The underlying mechanism revealed that Tec stabilizes MCL1, a key regulator of mitochondrial integrity, by promoting its deubiquitination through USP9X, thus preventing its degradation without relying on the PI3K-AKT signaling pathway. Notably, silencing either MCL1 or USP9X negated the anti-hypertrophic and antioxidant effects of Tec, underscoring their critical roles in this process. These findings position Tec as a novel modulator of the USP9X-MCL1-mitochondria axis, suggesting a new therapeutic approach to separate pathological remodeling from mitochondrial dysfunction in cardiac hypertrophy. By circumventing traditional survival pathways, Tec represents a mitochondria-focused strategy to slow the progression of heart failure, linking the pharmacology of natural compounds with the resilience of targeted organelles.

Mitochondrial dysfunction is increasingly recognized as a pivotal driver of cardiomyocyte apoptosis and cardiac deterioration following myocardial infarction (MI). This study identifies a significant upregulation of DDX60 in cardiomyocytes under hypoxic conditions. Elevated DDX60 levels enhance mitochondrial function and attenuate cardiomyocyte apoptosis in vitro, whereas its knockdown induces the opposite effects. In vivo, cardiomyocyte-specific DDX60 knockout markedly exacerbates mitochondrial dysfunction and apoptosis, accelerating post-MI cardiac remodeling and functional decline. Furthermore, we found that Arl2 knockdown partially negates the protective effects of DDX60 overexpression on ATP production and apoptosis. Conversely, adeno-associated virus-9 (AAV9)-mediated Arl2 overexpression partially restores cardiac function, reduces infarct size, and rescues mitochondrial integrity in DDX60 CKO mice post-MI. Mechanistically, DDX60 forms a translational complex with eukaryotic translation initiation factor 4 gamma 1 (EIF4G1) that enhances Arl2 mRNA translation, a process essential for mitochondrial homeostasis. Collectively, these findings establish DDX60 as a key regulator of cardioprotection post-MI by enhancing Arl2 translation, highlighting its potential as a therapeutic target for ischemic heart disease.