Wang Zhao, Li Lin, Yang Meng, Li Biao, Hu Siyuan
School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, China.
School of Physical Science, Hefei Normal University, Hefei 230061, China.
Int J Mol Sci. 2025 Apr 10;26(8):3550. doi: 10.3390/ijms26083550.
This study systematically elucidates the regulatory mechanisms and potential therapeutic value of the exercise-induced hormone Irisin in the pathological progression of cardiac fibrosis. Through comprehensive analysis and multidimensional data integration, we constructed a complete regulatory network of Irisin within the cardiovascular system, spanning its secretion, signal transduction, and precise regulatory control. Our findings demonstrate that exercise intervention significantly elevates circulating Irisin levels via the skeletal muscle-peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)-fibronectin type III domain-containing protein 5 (FNDC5) signaling axis. Irisin establishes a multidimensional molecular barrier against cardiac fibrosis by targeting Sirtuin 1 (Sirt1) activation, inhibiting the transforming growth factor-beta (TGF-β)/Smad3 signaling pathway, and modulating the transcriptional activity of the mitochondrial biogenesis core factors PGC-1α and nuclear respiratory factor 1 (NRF-1). Moreover, the dual regulatory mechanism of the exercise-skeletal muscle-heart axis not only effectively suppresses the aberrant activation of cardiac fibroblasts but also significantly reduces collagen deposition, oxidative stress, and inflammatory infiltration by restoring mitochondrial dynamics balance. Taken together, this study reveals a novel exercise-mediated cardioprotective mechanism at the molecular interaction network level, thereby providing a theoretical basis for the development of non-pharmacological bio-intervention strategies targeting the Irisin signaling pathway and laying a translational foundation for precise exercise prescriptions in cardiovascular diseases.
本研究系统地阐明了运动诱导的鸢尾素在心脏纤维化病理进展中的调控机制和潜在治疗价值。通过综合分析和多维度数据整合，我们构建了心血管系统内鸢尾素完整的调控网络，涵盖其分泌、信号转导和精确调控。我们的研究结果表明，运动干预通过骨骼肌-过氧化物酶体增殖物激活受体γ辅激活因子1α（PGC-1α）-含III型纤连蛋白结构域蛋白5（FNDC5）信号轴显著提高循环鸢尾素水平。鸢尾素通过靶向激活沉默调节蛋白1（Sirt1）、抑制转化生长因子-β（TGF-β）/Smad3信号通路以及调节线粒体生物合成核心因子PGC-1α和核呼吸因子1（NRF-1）的转录活性，建立了针对心脏纤维化的多维分子屏障。此外，运动-骨骼肌-心脏轴的双重调控机制不仅有效抑制心脏成纤维细胞的异常激活，还通过恢复线粒体动力学平衡显著减少胶原蛋白沉积、氧化应激和炎症浸润。综上所述，本研究在分子相互作用网络水平揭示了一种新的运动介导的心脏保护机制，从而为开发针对鸢尾素信号通路的非药物生物干预策略提供理论依据，并为心血管疾病的精确运动处方奠定转化基础。
