6‴‐Feruloylspinosin ameliorates pressure overload‐induced heart failure with comorbid insomnia through the activation of RORα

BACKGROUND AND PURPOSE: Targeting the retinoid-related orphan receptor α (RORα) signalling pathway represents a promising therapeutic strategy for cardiovascular diseases comorbid with insomnia. Here, we identify 6‴-feruloylspinosin (6-FS) as a potent RORα activator and investigate its therapeutic efficacy and underlying mechanisms in HF accompanied by insomnia. EXPERIMENTAL APPROACH: Transverse aortic constriction (TAC) was conducted to induce heart failure comorbid with insomnia. Echocardiography, histopathology and serum biochemical indicators were examined. Transcriptomics analysis, molecular docking, surface plasmon resonance binding assays, cellular thermal shift and microscale thermophoresis assays were performed. Subsequently, the mechanisms underlying 6-FS-mediated protection were elucidated through Western blot (WB), immunofluorescence (IF) and immunohistochemistry (IHC). KEY RESULTS: 6‴-Feruloylspinosin (6-FS) effectively improved cardiac function and mitigated myocardial injury in the mice model of TAC-induced HF. 6-FS attenuated pressure overload-induced cardiac hypertrophy and significantly improved insomnia and anxiety-like behaviours through modulation of neurotransmitter systems. 6-FS ameliorated insomnia through restoration of tight junction integrity and suppression of neuroinflammation. Mass spectrometry analysis confirmed the presence of 6-FS in both cardiac and cerebral tissues, and transcriptomic analysis demonstrated a marked up-regulation of RORα following 6-FS administration. Mechanistically, 6-FS exhibited the strongest binding affinity for RORα and simultaneously enhanced RORα-mediated regulation of the JAK2/STAT3 signalling pathway. Importantly, RORα inhibition completely abrogated the protective effects of 6-FS against TAC-induced cardiac hypertrophy and insomnia. CONCLUSIONS AND IMPLICATIONS: Our findings highlight 6-FS as a novel RORα activator with dual cardioprotective and sleep-enhancing benefits, offering new insights into the prevention and treatment of cardiovascular diseases with comorbid sleep disturbances.