Abstract 4339045: CREG1 Alleviates Sorafenib-Induced Cardiotoxicity via the Modulation of Necroptosis

Introduction: Sorafenib (Sor), a chemotherapeutic agent widely used in the treatment of various cancers. However, its clinical application has been limited by cardiotoxicity and adverse effects on cardiac function. Cellular Repressor of E1A-Stimulated Genes 1 (CREG1), an endogenous lysosomal protein, has been implicated in cardioprotection and various physiological processes in the heart, but its role in Sor-induced cardiotoxicity remains unexplored. Hypothesis: The present study aimed to comprehensively investigate the role and mechanism of action of CREG1 in the development of Sor-induced cardiotoxicity. Methods: Single-cell RNA sequencing (scRNA-seq) was performed on cardiac tissues from Sor-treated mice to identify key regulatory molecules involved in cardiotoxicity. Cardiomyocyte-specific CREG1 knockout (CREG1-CKO) and adeno-associated virus-mediated cardiac overexpression models were established to explore the function of CREG1 in the heart. Additionally, the mechanism of CREG1 in Sor-induced cardiotoxicity was further explored by stimulating cultured cardiomyocytes with Sor. Furthermore, the anti-tumor effects of CREG1 were validated in HepG2 xenografts to assess its potential therapeutic impact. Results: Our scRNA-seq analysis revealed cardiomyocytes as the predominant cellular targets in Sor-induced cardiotoxicity, with CREG1 emerging as a key hub gene inversely associated with cardiac injury. CREG1-CKO exacerbated cardiac dysfunction, myocardial fibrosis and hypertrophy, and aggravated necroptosis in Sor-treated mice. Conversely, CREG1 overexpression demonstrated opposite effects. We identified TYK2 as a direct binding partner of CREG1. Mechanistically, CREG1 was found to promote TYK2 protein degradation via the lysosomal pathway, thereby reducing STAT1 activation and alleviating necroptosis. The protective effect of CREG1 on necroptosis was reversed upon TYK2 overexpression. Notably, CREG1 overexpression was found to enhance the anti-hepatocellular carcinoma effect of Sor in HepG2 xenografts, suggesting its potential to improve the therapeutic efficacy of Sor. Conclusion: This study identifies CREG1 as a novel regulator of necroptosis that mitigates sorafenib-induced cardiotoxicity via inhibition of the TYK2-STAT1 pathway. The dual benefits of CREG1 augmentation include cardioprotection and enhanced antitumor efficacy. These findings offer novel insights into the application of CREG1 as a therapeutic target for Sor-induced cardiotoxicity.