Prospective associations of premature senescence, inflammation, and MERCSs in the cardioprotective effect of CBD in HFpEF.

Silva-Palacios A.; Zúñiga-Muñoz A.; Soria-Castro E.; Álvarez-León E.; García-Niño W.; Navarrete-Anastasio G.; Raza D.; Aparicio-Trejo O.; Ramírez-Carreto R.; Salas-Venegas V. et al. · Journal of molecular medicine (Berlin, Germany) · 2026

**Background & Methods** This preclinical study investigated cannabidiol (CBD) effects in a murine model of heart failure with preserved ejection fraction (HFpEF) induced by high-fat diet and L-NAME administration over 8 weeks. Multiple assessment modalities including invasive hemodynamic measurements, histological analysis, oxidative stress markers, immunofluorescence, RT-qPCR, and transmission electron microscopy were employed to evaluate cardiac structure and function. **Key Findings** • CBD treatment improved cardiac fibrosis and diastolic dysfunction but failed to reduce cardiac hypertrophy in HFpEF mice, with hemodynamic improvements assessed via pressure-volume loop analysis. • CBD markedly reduced accumulation of senescent cells and systemic cytokine levels associated with senescence-associated secretory phenotype (SASP), suggesting a mechanism linking cellular senescence to HFpEF pathology. • CBD suppressed NLRP3-mediated proinflammatory signaling through preservation of mitochondria-endoplasmic reticulum contact sites (MERCSs) integrity and inter-organelle distance, representing the first demonstration of CBD modulating inter-organelle communication in this context. **Dosage & Administration** CBD was administered subcutaneously every three days; specific dosing amount not reported. **Safety & Adverse Effects** Not reported. **Evidence Quality** This study represents early-stage preclinical research in a rodent disease model, limiting direct translational applicability to human HFpEF. The murine model may not fully recapitulate human HFpEF pathophysiology, which is primarily associated with aging and comorbidities. Key limitations include lack of data on cardiac hypertrophy improvement, absence of mechanistic characterization of signaling pathways underlying the MERCS-mediated protective effects, and animal-only evidence. The authors acknowledge that signaling mechanisms require further investigation. As a single preclinical study without clinical validation, this represents low-level evidence requiring substantial additional research before clinical recommendations can be formulated. Therapeutic potential in human HFpEF patients remains speculative pending human trials.

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