Cinnamaldehyde Ameliorates Ischemic Heart Failure by Targeting USP18 to Inhibit β1-Adrenergic Receptor Ubiquitination and Suppress TAK1/NF-κB Signaling Pathway

. To do so, a hypoxic injury model was established using AC16 cells, and male C57BL/6J mice underwent left anterior descending (LAD) artery ligation for eight weeks before receiving varying doses of cinnamaldehyde from the fourth week onward. Cardiac function and morphology were assessed via M-mode echocardiography, H&E staining, and Masson staining. Western blotting, co-immunoprecipitation (IP) assays, cellular thermal shift assay (CETSA), drug affinity responsive target stability (DARTS) analysis, and siRNA transfection were employed to evaluate the mechanism. Cinnamaldehyde significantly improved cardiac function, ameliorated cardiac fibrosis, and reduced myocardial inflammation in LAD-induced IHF mice. Concurrently, it protected cardiomyocytes and inhibited the inflammatory response in oxygen-glucose-deprived (OGD)-treated AC16 cells. Mechanistically, cinnamaldehyde was directly bound to USP18 and thus upregulated its expression. Further investigation revealed that cinnamaldehyde inhibited Formula: see text-adrenergic receptor (Formula: see text-AR) ubiquitination, thereby increasing its protein level. It also suppressed the TAK1/NF-κB pathway. Crucially, silencing USP18 eliminated both the cardioprotective and anti-inflammatory effects of cinnamaldehyde while also halting the inhibition of both Formula: see text-AR ubiquitination and the TAK1/NF-κB pathway. Cinnamaldehyde thus collectively enhances cardiac function against IHF by upregulating USP18 to thereby subsequently suppress both Formula: see text-AR ubiquitination and the activation of the TAK1/NF-κB pathway.