CIRKIL Assembles the PKM2 Homotetramer to Exacerbate Myocardial Fibrosis after Myocardial Infarction

Wei Yuan; Yizheng Wang; Bo Meng; Xiaoxuan Zhu; Xi Xu; Yiming Yao; Ying Yue; Zhongrui Tian; Jiangqi Liu; Jin Han; Jialiang Li; Xiaoxi Hu; Zhenbo Yang; Jinyun Guo; Ying Yang; Yang Zhang; Zhiguo Wang; Yuting Zhuang; Zhenwei Pan; Baofeng Yang; Yanjie Lu

doi:10.1016/j.eng.2026.05.012

Engineering ›› :202605012 DOI: 10.1016/j.eng.2026.05.012

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CIRKIL Assembles the PKM2 Homotetramer to Exacerbate Myocardial Fibrosis after Myocardial Infarction

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Abstract

During the healing phase after myocardial infarction (MI), various stimulatory factors activate the transformation of cardiac fibroblasts (CFs) into myofibroblasts, leading to collagen synthesis and cardiac fibrosis. Here, we investigated the role of the cardiac ischemia reperfusion-associated Ku70-interacting long noncoding RNA (CIRKIL) in post-MI cardiac fibrosis and the underlying molecular mechanisms. Cardiac fibrotic tissue from MI mice and transforming growth factor-b (TGF-b1)-treated CFs exhibited elevated expression of CIRKIL in the cytosol of the CFs. Furthermore, CIRKIL gain-of-function exacerbated MI-induced cardiac fibrosis in transgenic mice, whereas CIRKIL deficiency alleviated this fibrotic progression. Consistently, CIRKIL overexpression promoted the proliferation and transformation of CFs, resulting in the upregulation of collagen type I and type III, whereas CIRKIL silencing had the opposite effects. Mechanistically, CIRKIL functioned as a molecular scaffold that facilitated the functional oligomerization of the pyruvate kinase M2 (PKM2) homotetramer, which binds to Smad7 and inhibits Smad7-mediated ubiquitination and degradation of TGF-b type I receptor (TGFBR1), a critical profibrotic factor in the TGF-b signaling pathway. Importantly, the regulatory effects of the functional fragment of CIRKIL on PKM2 homotetramer formation and CF activation were similar to those of full-length CIRKIL. Our findings revealed that CIRKIL, as a molecular scaffold, facilitates the assembly of the PKM2 homotetramer, which inhibits the Smad7-mediated ubiquitination and degradation of TGFBR1 and results in CF activation and cardiac fibrosis in mouse MI hearts, indicating that CIRKIL might be a promising intervention target for cardiac fibrosis-related diseases.

Keywords

CIRKIL / Cardiac fibrosis / Pyruvate kinase M2 / Tetramer / Myocardial infarction

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Wei Yuan, Yizheng Wang, Bo Meng, Xiaoxuan Zhu, Xi Xu, Yiming Yao, Ying Yue, Zhongrui Tian, Jiangqi Liu, Jin Han, Jialiang Li, Xiaoxi Hu, Zhenbo Yang, Jinyun Guo, Ying Yang, Yang Zhang, Zhiguo Wang, Yuting Zhuang, Zhenwei Pan, Baofeng Yang, Yanjie Lu. CIRKIL Assembles the PKM2 Homotetramer to Exacerbate Myocardial Fibrosis after Myocardial Infarction. Engineering 202605012 DOI:10.1016/j.eng.2026.05.012

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