哈尔滨医科大学杨宝峰团队在研究中取得进展。他们的论文发现了含有Sarm1的染色体外环状DNA通过TGF-β/Smad激活促进衰老相关的心脏纤维化。2026年3月2日出版的《分子细胞生物学报》杂志发表了这项成果。

结合eccDNA的注释和转录组中发现的与衰老相关的关键基因，课题组研究人员发现了含有1（Sarm1）的无菌α和TIR基序，Sarm1是位于eccDNA中的NAD⁺代谢和神经退行性变的关键调节因子，是通过促纤维化信号传导导致心脏衰老的新驱动因素。在老年小鼠中，Sarm1敲低可显著恢复心功能并减少纤维化。相反，在过表达Sarm1的年轻转基因小鼠中，Sarm1加速了心脏老化表型。机制上，免疫共沉淀联合质谱鉴定TGF -β-Smad2/3是主要途径，SIS3的药理抑制消除了sarm1驱动的Smad2/3磷酸化。他们的研究结果表明，含有Sarm1的eccDNA通过TGF -β-Smad2/3通路放大促纤维化信号来驱动心脏衰老，提出清除eccDNA和抑制Sarm1是治疗衰老相关心脏纤维化的新策略。

据了解，心脏老化与进行性心脏纤维化和功能障碍有关，但其潜在机制仍不完全清楚。据报道，染色体外环状DNA （eccDNA）参与肿瘤和年龄相关的基因组不稳定性，而其在衰老过程中心脏纤维化的作用仍有待充分阐明。在这项研究中，环状DNA测序和RNA测序分析了年轻和老年心脏组织的eccDNA谱。老年小鼠心脏组织中eccDNA的数量明显高于年轻小鼠。

附：英文原文

Title: Sarm1-containing extrachromosomal circular DNA promotes aging-associated cardiac fibrosis via TGF-β/Smad activation

Author: Zhang, Ying, Wang, Siyu, Liu, Jie, Du, Zhiyuan, Yin, Chenchen, Fan, Shasha, Li, Haodong, Wang, Hao, Zhang, Yanwei, Su, Pengyao, Zhang, Mengfan, Xuan, Lina, Zhang, Mingyu, Sun, Lihua, Jiao, Lei, Dong, Yanyan, Wang, Xu, Gong, Manyu, Yang, Baofeng, Zhang, Ying

Issue&Volume: 2026-03-02

Abstract: Cardiac aging is associated with progressive cardiac fibrosis and dysfunction, yet the underlying mechanisms remain incompletely understood. Extrachromosomal circular DNA (eccDNA) has been reported to participate in tumor and age-related genomic instability, while its role in cardiac fibrosis during aging remains to be fully elucidated. In this study, circular DNA sequencing and RNA seqencing were performed to analyze eccDNA profiles in young and aged cardiac tissues. The number of eccDNAs in the cardiac tissue of aged mice is higher than that in young mice. Combining the annotation of eccDNAs and the key genes related to aging identified in the transcriptome, we identified sterile alpha and TIR motif containing 1 (Sarm1), a key regulator of NAD+ metabolism and neurodegeneration located in eccDNAs, as a novel driver of cardiac aging via pro-fibrotic signaling. In aged mice, Sarm1 knockdown significantly restored cardiac function and reduced fibrosis. Conversely, Sarm1 accelerated cardiac aging phenotypes in young Sarm1-overexpressing transgenic mice. Mechanistically, co-immunoprecipitation combined with mass spectrometry identified TGF-β–Smad2/3 as the dominant pathway, with pharmacological inhibition by SIS3 abolishing Sarm1-driven Smad2/3 phosphorylation. Our findings reveal that Sarm1-containing eccDNA drives cardiac aging by amplifying pro-fibrotic signaling through the TGF-β–Smad2/3 pathway, proposing eccDNAs clearance and Sarm1 inhibition as novel therapeutic strategies for aging-related cardiac fibrosis.

DOI: 10.1093/jmcb/mjag005

Source: https://academic.oup.com/jmcb/advance-article/doi/10.1093/jmcb/mjag005/8503497searchresult=1