Syringin Protects Against Doxorubicin‐Induced Cardiotoxicity via Apelinr‐Dependent Activation of the Nuclear Factor‐Erythroid 2‐Related Factor 2/Heme Oxygenase‐1 Antioxidant Pathway

Cardiotoxicity induced by the chemotherapeutic agent Doxorubicin (Dox) is a major clinical challenge, primarily mediated by overwhelming oxidative stress. While Syringin (Syr) is known for its antioxidant potential, its efficacy and mechanism in the context of Dox-induced cardiotoxicity are not well defined. This study aimed to assess the therapeutic potential of Syr in alleviating Dox-induced cardiac injury and to elucidate its underlying molecular mechanism. The cardioprotective effect of Syr was evaluated in a Dox-induced mouse model of cardiotoxicity and in primary cardiomyocytes, with pravastatin (Prv, 10 mg/kg) serving as the positive control in the Syr dose-finding experiment. Cardiac function and myocardial strain were measured by advanced echocardiography using wall-tracking and speckle-tracking analyses. Network pharmacology was applied to identify downstream signaling pathways and molecular targets of Syr. Myocardial atrophy, antioxidant proteins, and oxidative stress markers were assessed by histology, Western blotting, and qRT-PCR. To validate the key molecular target, in vivo siRNA-mediated knockdown of the apelin receptor (APJ) was performed. Syr treatment significantly attenuated myocardial atrophy and suppressed oxidative stress. Syr also increased APJ expression, activated mechanosensitive PI3K/AKT phosphorylation, and restored fibroblast growth factor 21 (FGF21) homeostasis, thereby improving myocardial circumferential and longitudinal strain. Mechanistically, APJ silencing blunted Syr's ability to upregulate antioxidant proteins in Dox-exposed cardiomyocytes, and the benefits of FGF21 overexpression were lost. Consistently, APJ knockdown abolished Syr's protection against Dox-induced cardiotoxicity in vivo, eliminating its improvements in cardiac function and myocardial strain. Our study first demonstrates that Syr protects against Dox-induced cardiotoxicity by restoring the APJ/PI3K/AKT signaling axis, which subsequently enhances the nuclear factor-erythroid 2-related factor 2/heme oxygenase-1 (NRF2/HO-1) antioxidant response and maintains FGF21 homeostasis. These findings identify Syr as a promising natural compound for mitigating chemotherapy-induced cardiotoxicity and highlight the APJ as a novel therapeutic target.