苏尼替尼调控CTGF经自噬降解的分子机制及在其心脏毒性中的作用研究

Sunitinib, a first-line treatment of late stage renal carcinoma and other solid tumors, extends more than one hundred thousand survivals of patients per year. High rate and lethality of cardiotoxicity limited its long-time and safe clinical application. Our previous finding that autophagy is the major risk factor for sunitinib-induced cardiotoxicity has gained wide attention, while the molecular mechanism remains elusive and needs to be closely examined. Given this, we provide evidence that sunitinib-induced cardiomyocytes autophagy could specifically stimulate degradation of connective tissue growth factor (CTGF), which causes significant damage to myocardium, and potentially it is triggered by autophagy initiation factor high mobility group box 1 (HMGB1). Based on this, we wish to further clarify the contribution of autophagic degradation of CTGF to suntinib-induced cardiotoxicity, declare the relation between CTGF and myocardial cell survival, reveal the possible mechanisms underlying the cardiotoxicity of sunitinib by stimulating autophagy lysosome-dependent degradation of CTGF in the assistance of autophagy cargo protein p62, explain how HMGB1 activates autophagy degradation of CTGF and causes myocardial dysfunction, and attempt to eliminate the cardiotoxicity of sunitinib by interfering HMGB1-CTGF signaling pathway. Therefore, we will not only provide new insights into the molecular mechanism of sunitinib-induced cardiotoxicity, and firstly clarify the biological function on myocardial cell survival of CTGF and how autophagy regulates the degradation of it, but also test the feasibility of anti-cardiotoxicity treatment to sunitinib via HMGB1-CTGF axis, provide the potential target and theoretical basis for design and discovery novel therapeutic intervention of drug induced-cadiotoxicity.

苏尼替尼是临床治疗晚期肾癌等多种实体瘤的一线药物，每年超过十万患者从中获益，但严重的心脏毒性限制了其长期安全使用。我们前期报道自噬是苏尼替尼心脏毒性的关键因素，受到同行关注，但其具体的分子机制仍不清楚。后续，我们又发现CTGF的自噬溶酶体降解在苏尼替尼心脏毒性中发挥了关键作用，自噬激活因子HMGB1可能参与这一过程。基于此，本课题将明确CTGF自噬溶酶体降解在苏尼替尼心脏毒性中的作用，阐明CTGF维持心肌细胞存活的关键作用，并进一步研究苏尼替尼作用下CTGF经由自噬Cargo蛋白p62转运进入自噬溶酶体发生降解的分子过程，阐明HMGB1参与调控CTGF自噬溶酶体降解的作用机制，探索HMGB1-CTGF作为干预苏尼替尼心脏毒性靶点的可能性。通过本课题的研究，不仅将阐明苏尼替尼心脏毒性的全新分子机制，发现CTGF蛋白的新功能及其降解新途径，还可为临床克服苏尼替尼的心脏毒性提供新策略。

苏尼替尼是晚期肾癌等多种实体瘤的一线药物，在肿瘤治疗中举足轻重。然而，近年来研究发现长期使用苏尼替尼会对患者心脏产生明显的毒副作用，甚至可以引起死亡，严重限制其临床应用，然而其心脏毒性发生机制尚不明确。因此深入探索苏尼替尼心脏毒性的分子机制、确定毒性干预靶点并制定有效干预策略显得尤为重要。本项目的研究确证了致死性自噬促进苏尼替尼心脏毒性的关键作用，明确了心功能蛋白CTGF的自噬溶酶体途径降解是造成苏尼替尼心脏毒性的主要原因。进一步的研究表明HMGB1是苏尼替尼诱导诱导心肌细胞自噬的关键调控分子，其抑制剂甘草酸可显著减轻苏尼替尼引起的心肌细胞死亡和心脏毒性。本项目的研究，不仅阐明了苏尼替尼心脏毒性的全新分子机制，明确了致死性自噬在药源性心脏毒性中的关键调控作用，发现了CTGF蛋白调控心肌细胞存活与心脏功能的新功能及其降解新途径，还为临床克服苏尼替尼的心脏毒性提供靶点与有效干预策略。