2. Academic Validation
  3. Lithospermic acid alleviates myocardial ischemia/reperfusion injury by inhibiting mitophagy via the Piezo1-PPP3/calcineurin-TFEB pathway

Lithospermic acid alleviates myocardial ischemia/reperfusion injury by inhibiting mitophagy via the Piezo1-PPP3/calcineurin-TFEB pathway

  • Phytomedicine. 2025 Oct 11:148:157402. doi: 10.1016/j.phymed.2025.157402.
Xin Chen 1,  Honglin Xu 2,  Zhongyang Yu 2,  Shujin Pang 1,  Ruixue Chen 1,  Shangfei Luo 3,  Xianmei Pan 4,  Rentao Wan 1,  Youfen Yao 1,  Xiaoting Chen 1,  Qiaorui Tan 1,  Bin He 1,  Yajuan An 1,  Lingjun Wang 5,  Yining Guo 6,  Jing Li 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Traditional Chinese Medicine Syndromes, The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510000, China; Lingnan Medical Research Center, Guangzhou Clinical Research Academy of Chinese Medicine, Guangzhou, Guangdong 510000, China; Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510000, China.
  • 2 Dongguan Hospital, Guangzhou University of Chinese Medicine, Dongguan, Guangdong 523000, China.
  • 3 Innovation Research Center, Shandong University of Chinese Medicine, Jinan, Shandong 250307, China.
  • 4 Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Shenzhen, Guangdong 518104, China.
  • 5 State Key Laboratory of Traditional Chinese Medicine Syndromes, The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510000, China; Lingnan Medical Research Center, Guangzhou Clinical Research Academy of Chinese Medicine, Guangzhou, Guangdong 510000, China; Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510000, China. Electronic address: smu868@gzucm.edu.cn.
  • 6 Dongguan Hospital, Guangzhou University of Chinese Medicine, Dongguan, Guangdong 523000, China. Electronic address: guoyining400@gmail.com.
  • 7 State Key Laboratory of Traditional Chinese Medicine Syndromes, The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510000, China; Lingnan Medical Research Center, Guangzhou Clinical Research Academy of Chinese Medicine, Guangzhou, Guangdong 510000, China; Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510000, China; Innovation Research Center, Shandong University of Chinese Medicine, Jinan, Shandong 250307, China; School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, LS2 9JT, UK. Electronic address: bmsjingl@gzucm.edu.cn.
PMID: 41101069 DOI: 10.1016/j.phymed.2025.157402
Abstract

Introduction: Myocardial ischemia/reperfusion injury poses a human health threat, and lithospermic acid (LA) has shown potential as a therapeutic agent.

Objectives: To investigate the preventive effects of LA and elucidate its modulation of Piezo-Type Mechanosensitive Ion Channel Component 1 .

Methods: Cardiac function was evaluated using cardiac ultrasound, Evans blue/TTC staining, and hematoxylin-eosin staining. To evaluate the effects of LA on cardiomyocyte inflammation, Necroptosis, and Mitophagy, we performed immunofluorescence, Western blotting, flow cytometry, and RT-qPCR. Additionally, RNA Sequencing, cellular thermal shift assay, small molecule agonists/inhibitors, and cardiomyocyte-specific Piezo1 knockout mice were employed to further elucidate the molecular mechanisms and confirm that LA targeted Piezo1 to alleviate myocardial I/R injury.

Results: LA treatment markedly ameliorated myocardial I/R injury. This improvement correlated with reduced inflammation, decreased accumulation of Reactive Oxygen Species, attenuated cardiomyocyte Necroptosis, and inhibited Mitophagy. Mechanistically, LA reduced calcium influx and inhibited Mitophagy in cardiomyocytes, which contributed to the observed alleviation of inflammation, lower ROS levels, and decreased cell necrosis. Further studies revealed that LA targeted Piezo1, suppressing calcium influx, decreasing Calcineurin activity, and modulating nuclear translocation of transcription factor EB to inhibit Mitophagy. Notably, the beneficial effects of LA on myocardial I/R injury were partially abolished in Piezo1 cardiomyocyte-specific knockout mice, underscoring the crucial role of Piezo1 in mediating the therapeutic effects of LA.

Conclusion: These findings highlight LA is a prospective therapeutic agent to improve cardiac function after myocardial I/R injury, offering a new direction for regulating Piezo1.

Keywords

Lithospermic acid; Mitophagy; Myocardial ischemia/reperfusion injury; Piezo1; TFEB.

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