2. Academic Validation
  3. Formononetin, a bioactive isoflavone compound in modified nuanxinkang, alleviates cardiorenal syndrome type 4-induced mitochondrial dysfunction by targeting Hippo-YAP signaling

Formononetin, a bioactive isoflavone compound in modified nuanxinkang, alleviates cardiorenal syndrome type 4-induced mitochondrial dysfunction by targeting Hippo-YAP signaling

  • Phytomedicine. 2025 Aug 15:147:157152. doi: 10.1016/j.phymed.2025.157152.
Meidan Yao 1,  Ruijia Wen 2,  Haowen Zhuang 1,  Yihua Li 3,  Xiaohua Lin 4,  Shujin Pang 1,  Jingyue Zhang 1,  Zhuoji Guan 5,  Birong Liang 5,  Huan Li 5,  Yusheng Huang 5,  Lingjun Wang 6,  Junyan Wang 7,  Xin Dong 8
Affiliations

Affiliations

  • 1 The First Affiliated Hospital, Guangzhou University of Chinese Medicine, No. 16 Airport Road, Baiyun District, Guangzhou 510006, China; Guangzhou University of Chinese Medicine, Guangzhou, No. 12 Airport Road, Baiyun District, Guangzhou 510006, China; National Key Laboratory of Chinese Medicine Symptoms, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Guangzhou Key Laboratory of Chinese Medicine for Prevention and Treatment of Chronic Heart Failure, Guangzhou University of Chinese Medicine, Guangzhou 510006, China.
  • 2 The First Affiliated Hospital, Guangzhou University of Chinese Medicine, No. 16 Airport Road, Baiyun District, Guangzhou 510006, China; Guangzhou University of Chinese Medicine, Guangzhou, No. 12 Airport Road, Baiyun District, Guangzhou 510006, China; National Key Laboratory of Chinese Medicine Symptoms, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No. 12 Airport Road, Baiyun District, Guangzhou 510006, China; Institute of Formula and Syndrome, Guangzhou University of Chinese Medicine, Guangzhou 510006, China.
  • 3 The First Affiliated Hospital, Guangzhou University of Chinese Medicine, No. 16 Airport Road, Baiyun District, Guangzhou 510006, China.
  • 4 Guangzhou University of Chinese Medicine, Guangzhou, No. 12 Airport Road, Baiyun District, Guangzhou 510006, China.
  • 5 The First Affiliated Hospital, Guangzhou University of Chinese Medicine, No. 16 Airport Road, Baiyun District, Guangzhou 510006, China; Guangzhou University of Chinese Medicine, Guangzhou, No. 12 Airport Road, Baiyun District, Guangzhou 510006, China; National Key Laboratory of Chinese Medicine Symptoms, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Guangdong Provincial Clinical Research Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Guangzhou Key Laboratory of Chinese Medicine for Prevention and Treatment of Chronic Heart Failure, Guangzhou University of Chinese Medicine, Guangzhou 510006, China.
  • 6 The First Affiliated Hospital, Guangzhou University of Chinese Medicine, No. 16 Airport Road, Baiyun District, Guangzhou 510006, China; Guangzhou University of Chinese Medicine, Guangzhou, No. 12 Airport Road, Baiyun District, Guangzhou 510006, China; National Key Laboratory of Chinese Medicine Symptoms, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Guangdong Provincial Clinical Research Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Guangzhou Key Laboratory of Chinese Medicine for Prevention and Treatment of Chronic Heart Failure, Guangzhou University of Chinese Medicine, Guangzhou 510006, China. Electronic address: smu868@163.com.
  • 7 The First Affiliated Hospital, Guangzhou University of Chinese Medicine, No. 16 Airport Road, Baiyun District, Guangzhou 510006, China; Guangzhou University of Chinese Medicine, Guangzhou, No. 12 Airport Road, Baiyun District, Guangzhou 510006, China; National Key Laboratory of Chinese Medicine Symptoms, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No. 12 Airport Road, Baiyun District, Guangzhou 510006, China; Institute of Formula and Syndrome, Guangzhou University of Chinese Medicine, Guangzhou 510006, China. Electronic address: junyan_wang@163.com.
  • 8 The First Affiliated Hospital, Guangzhou University of Chinese Medicine, No. 16 Airport Road, Baiyun District, Guangzhou 510006, China; Guangzhou University of Chinese Medicine, Guangzhou, No. 12 Airport Road, Baiyun District, Guangzhou 510006, China. Electronic address: 844539862@qq.com.
PMID: 40850069 DOI: 10.1016/j.phymed.2025.157152
Abstract

Background: Cardiorenal syndrome type 4 (CRS4) arises from the chronic kidney disease, and currently, there is a lack of therapies specifically target the dual pathological mechanisms of CRS4, namely mitochondrial dysfunction and maladaptive remodeling. In the present study, our aim was to determine the effectiveness of the herbal formulation modified nuanxinkang (MNXK) and its isoflavone formononetin (FNT) on CRS4.

Methods: CRS4 was modeled in C57BL/6 mice through 5/6 nephrectomy and subsequently treated with MNXK or FNT for 12 weeks, and the cardiac function, histopathology, and mitochondrial ultrastructure were evaluated. To identify the potential targets, network pharmacology, transcriptomics, and molecular dynamic simulations were conducted. Additionally, CRS4 injury was induced in HL-1 cardiomyocytes using uremic serum.

Results: MNXK administration significantly improved cardiac function, as evidenced by enhanced ejection fraction, reduced myocardial injury, and restored mitochondrial cristae structure. FNT, the core bioactive component isolated from MNXK, exerted the protective function through directly binding to Yes-associated protein (YAP), thereby blocking nuclear translocation and suppressing the transcription of targets downstream of Hippo pathway. In cardiomyocytes, FNT was demonstrated to attenuate mitochondrial Reactive Oxygen Species (ROS), normalize mitochondrial dynamics, maintain mitochondrial morphology, and thereby enhance mitochondrial function. Additionally, YAP knockdown did not further enhance these beneficial effects. Noticeable, enforced overexpression of YAP abolished FNT-induced cardiac protection.

Conclusion: Our results demonstrated that MNXK and FNT mitigated CRS4 through activating Hippo-YAP signaling to block pro-fibrotic signal cascades and facilitating mitochondrial rescue via biogenesis and metabolic reprogramming. This study will provide more insights into the treatment of CRS4 with natural small molecule substances.

Keywords

CRS4; Formononetin; Hippo-YAP signaling pathway; MNXK; Mitochondrial function.

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