2. Academic Validation
  3. SD49-7 attenuates cardiac hypertrophy by upregulation of S100B through KDM4A inhibition

SD49-7 attenuates cardiac hypertrophy by upregulation of S100B through KDM4A inhibition

  • Biochem Pharmacol. 2025 Aug 8;242(Pt 1):117218. doi: 10.1016/j.bcp.2025.117218.
Zhenzhen Zhang 1,  Mingkai Gao 1,  Tengteng Yan 1,  Zian Feng 2,  Shengyuan Lu 1,  Lu Tang 1,  Xiaoqiang Li 3,  Wenjia Wang 3,  Pengcheng Yang 3,  Shuiping Zhou 3,  Yunhui Hu 4,  Yajun Duan 5,  Shuang Zhang 6
Affiliations

Affiliations

  • 1 Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China.
  • 2 Department of Cardiology, the First Affiliated Hospital of University of Science and Technology of China, Hefei, China.
  • 3 Tianjin Tasly Digital Intelligence Chinese Medicine Technology Co., Ltd., Tianjin, China.
  • 4 Tianjin Tasly Digital Intelligence Chinese Medicine Technology Co., Ltd., Tianjin, China. Electronic address: tsl-huyunhui@tasly.com.
  • 5 Department of Cardiology, the First Affiliated Hospital of University of Science and Technology of China, Hefei, China. Electronic address: yajunduan@ustc.edu.cn.
  • 6 Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China. Electronic address: zhangshuang@hfut.edu.cn.
PMID: 40784571 DOI: 10.1016/j.bcp.2025.117218
Abstract

Cardiac hypertrophy is a major contributor to heart failure, yet therapeutic options remain limited. Emerging evidence suggests that upregulated expression of histone lysine-specific demethylase 4A (KDM4A) in patients with cardiac hypertrophy may represent a significant, albeit underappreciated, disease risk factor; however, the underlying mechanism and specific downstream pathway remain unclear. In this study, we investigated the therapeutic effect of SD49-7, a specific KDM4A inhibitor, on cardiac hypertrophy and its underlying mechanism, utilizing both in vivo and in vitro models. Employed isoprenaline (ISO)-induced mouse model of cardiac hypertrophy in vivo, and stimulated rat cardiomyocytes (H9c2 cells) with ISO, phenylephrine (PE), angiotensin II (Ang II) in vitro. Echocardiography, histopathology analysis and serological indicators demonstrated that SD49-7 treatment significantly alleviated cardiac hypertrophy in ISO-treated mice. Furthermore, SD49-7 significantly inhibited the expression levels of hypertrophy markers ANP, BNP and β-MHC in stimulated H9c2 cells. Mechanistically, ATAC-seq results from mouse hearts revealed that the amelioration effects of SD49-7 on cardiac hypertrophy depend on S100B upregulation via KDM4A inhibition. Conversely, suppression of S100B expression in cardiomyocytes abolished the protective effects of SD49-7 against hypertrophy. In conclusion, our findings demonstrate that SD49-7 upregulates S100B expression in cardiomyocytes in a KDM4A-dependent manner, which in turn ameliorates the cardiac hypertrophic phenotypes. These results suggest that SD49-7 represents a promising therapeutic strategy for cardiac hypertrophy.

Keywords

Cardiac hypertrophy; Demethylation; KDM4A; S100B; SD49-7.

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