Heart failure remains one of the most pressing challenges in cardiovascular medicine. Heart failure is a cardiovascular disease (CVD) associated with inflammation, metabolic stress, including mitochondrial dysfunction, oxidative distress, impaired cellular resilience and myocardial fibrosis (Boulet et al., 2024). Despite major advances in pharmacological and device-based therapies, CVD patients with heart failure continue to experience ventricular dysfunction and adverse remodelling. Current treatments primarily target neurohormonal activation and haemodynamic load, yet increasing evidence suggests that intracellular stress responses within cardiomyocytes play a central role in disease progression. Mitochondrial dysfunction and oxidative distress, including the accumulation of reactive oxygen species (ROS), have emerged as key drivers of cardiac remodelling and contractile failure (Boulet et al., 2024). Mitochondrial dysfunction plays a central role in the pathogenesis of heart failure and myocardial fibrosis, which implies impaired mitochondrial respiration and overproduction of mitochondrial ROS that damages cellular proteins, lipids and DNA while simultaneously activating pro-inflammatory signalling pathways. Such a vicious cycle of mitochondrial dysfunction, oxidative distress, inflammation and cellular injury accelerates disease progression and myocardial fibrosis. Consequently interventions capable of restoring mitochondrial homeostasis represent an attractive therapeutic strategy in the context of heart failure. The mitochondrial 18 kDa translocator protein TSPO that is located in the mitochondrial outer membrane has been reported to be elevated in models of cardiac injury (Baglini et al., 2023). TSPO is involved in mitochondrial stress response, mitochondrial respiration, calcium transport, apoptosis regulation and inflammatory signalling. Studies have shown that cardiomyocyte-specific deletion of TSPO protects the heart against pressure overload–induced failure (Thai et al., 2018). In this context the work by Diloretto et al. extended these findings by demonstrating that chronic pharmacological inhibition of TSPO produced similar cardioprotective effects in a murine model of transverse aortic constriction–induced pressure overload and heart failure. The authors showed that the pharmacological inhibition of TSPO with the ligand Ro5-4864 significantly mitigated the structural and functional consequences of pressure overload, with significant preserved systolic function and reduced ventricular remodelling. In addition molecular markers associated with heart failure and myocardial fibrosis, including natriuretic peptide A, collagen alpha-1 and periostin, were significantly reduced in Ro5-4864-treated mice. Proteomic analyses further revealed broad changes in pathways associated with immune activation and oxidative distress. The study by Diloretto et al. identified the p62-Keap1 (Kelch-like ECH-associated protein 1)-Nrf2 (nuclear factor erythroid 2-related transcription factor) antioxidant pathway as a mediator of the cardioprotective effects of TSPO inhibition. Treatment with Ro5-4864 increases Nrf2 expression while reducing the levels of Keap1 and p62. This molecular shift is accompanied by the reprogramming of the glutathione system, and increased expression of antioxidant enzymes such as NAD(P)H quinone oxidoreductase-1 (NQO1) and superoxide dismutase-2 (SOD2), indicating the activation of antioxidant protective pathways. These findings reinforce the concept that heart failure is a disease characterized by chronic cellular distress and inflammatory signalling. From a translational perspective these findings warrant further investigation, including studies on other forms of heart failure at the preclinical level and clinical studies in humans. The effects of TSPO ligand Ro5-4864 in this context need to be confirmed in humans, because Ro5-4864 is a benzodiazepine 4′-chloro-derivative of diazepam which lacks affinity for GABA-A (GABA subtype A) receptors. In addition the work by Diloretto et al. illustrates how advances in pharmacological modulation of mitochondrial biology can inform new therapeutic strategies for CVD. Targeting mitochondrial stress responses may allow interventions to address disease mechanisms directly within cardiomyocytes rather than solely modulating systemic haemodynamics. Moreover restoring mitochondrial homeostasis helps preserve cardiomyocyte viability and limits adverse remodelling in pressure overload–induced heart failure. Strategies that target mitochondrial function and activate cellular antioxidant pathways, including Nrf2 signalling, may therefore complement existing heart failure therapies. Finally one blind box in this study remains a very important aspect to develop in the future: the implication of the reactive species interactome that includes ROS, reactive nitrogen (RNS), reactive sulphur species (RSS), redox enzymes and downstream redox molecules in heart failure from mice models to humans (Chatre, 2024). As our understanding of mitochondrial and redox signalling continues to evolve, therapies targeting mitochondrial stress pathways may become an important addition to the therapeutic arsenal against heart failure with an emerging paradigm: protecting the heart by restoring mitochondrial and redox resilience. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. None declared. L.C.: conception or design of the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work. The work was supported by the CNRS.
Laurent Châtre (Sun,) studied this question.