Hypertrophic cardiomyopathy (HCM) constitutes the most common genetic cardiac disorder. However, current pharmacotherapeutics are mainly symptomatic and only partially address underlying molecular mechanisms. Circular RNAs (circRNAs) are a recently discovered class of non-coding RNAs and emerged as specific and powerful regulators of cellular functions. By performing global circRNA-specific next generation sequencing in cardiac tissue of patients with hypertrophic cardiomyopathy compared to healthy donors, we identified circZFPM2 (hsa_circ_0003380). CircZFPM2, which derives from the ZFPM2 gene locus, is a highly conserved regulatory circRNA that is strongly induced in HCM tissue. In vitro loss-of-function experiments were performed in neonatal rat cardiomyocytes, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), and HCM-patient-derived hiPSC-CMs. A knockdown of circZFPM2 was found to induce cardiomyocyte hypertrophy and compromise mitochondrial respiration, leading to an increased production of reactive oxygen species and apoptosis. In contrast, delivery of recombinant circZFPM2, packaged in lipid-nanoparticles or using AAV-based overexpression, rescued cardiomyocyte hypertrophic gene expression and promoted cell survival. Additionally, HCM-derived cardiac organoids exhibited improved contractility upon CM-specific overexpression of circZFPM2. Multi-Omics analysis further promoted our hypothesis, showing beneficial effects of circZFPM2 on cardiac contractility and mitochondrial function. Collectively, our data highlight that circZFPM2 serves as a promising target for the treatment of cardiac hypertrophy including HCM.

肥厚型心肌病 （HCM） 是最常见的遗传性心脏病。然而，目前的药物治疗药物主要是对症治疗，仅部分解决潜在的分子机制。环状 RNA （circRNA） 是最近发现的一类非编码 RNA，是细胞功能的特异性和强大调节因子。与健康供体相比，通过在肥厚型心肌病患者的心脏组织中进行全局 circRNA 特异性下一代测序，我们确定了 circZFPM2 （hsa_circ_0003380）。CircZFPM2 来源于 ZFPM2 基因位点，是一种高度保守的调节性 circRNA，在 HCM 组织中被强烈诱导。在新生大鼠心肌细胞、人诱导多能干细胞来源的心肌细胞 （hiPSC-CM） 和 HCM 患者来源的 hiPSC-CMs 中进行了体外功能丧失实验。发现敲除 circZFPM2 会诱导心肌细胞肥大并损害线粒体呼吸，导致活性氧产生增加和细胞凋亡。相比之下，递送包装在脂质纳米颗粒中或使用基于 AAV 的过表达的重组 circZFPM2 可挽救心肌细胞肥大基因表达并促进细胞存活。此外，HCM 来源的心脏类器官在 CM 特异性过表达 circZFPM2 后表现出改善的收缩力。多组学分析进一步促进了我们的假设，显示 circZFPM2 对心脏收缩力和线粒体功能的有益影响。总的来说，我们的数据强调 circZFPM2 是治疗包括 HCM 在内的心脏肥大的有前途的靶点。