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，目前的药物治疗主要是针对症状的，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，并作为细胞功能的特定且强大的调节剂而出现。通过对肥厚型心肌病患者与健康供体的心脏组织进行全局 circRNA 特异性下一代测序，我们鉴定出了 circZFPM2 (hsa_circ_0003380)。 CircZFPM2源自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-CM 中进行了体外功能丧失实验。研究发现，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，包装在脂质纳米颗粒中或使用基于 AAV 的过表达的重组 circZFPM2 的递送，可以挽救心肌细胞肥大基因的表达并促进细胞存活。此外，HCM 衍生的心脏类器官在 circZFPM2 的 CM 特异性过度表达后表现出改善的收缩性。多组学分析进一步证实了我们的假设，显示了 circZFPM2 对心肌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希望的靶点。