2. Academic Validation
  3. Rosmarinic acid alleviates doxorubicin-induced cellular senescence and cardiotoxicity by targeting the 14-3-3/Foxo1 signaling axis

Rosmarinic acid alleviates doxorubicin-induced cellular senescence and cardiotoxicity by targeting the 14-3-3/Foxo1 signaling axis

  • Phytomedicine. 2025 Oct 26:148:157482. doi: 10.1016/j.phymed.2025.157482.
Chang Fan 1,  Jianxin Wu 2,  Senyang Hu 1,  Yi Xia 1,  Zhixi Wei 1,  Hejing Tang 1,  Wenhua Jin 1,  Zhenhua Zhang 2,  Peng An 1,  Junjie Luo 3,  Yongting Luo 4,  Yinhua Zhu 5
Affiliations

Affiliations

  • 1 Department of Nutrition and Health, China Agricultural University, Beijing 100193, China.
  • 2 College of Science, China Agricultural University, Beijing 100193, China.
  • 3 Department of Nutrition and Health, China Agricultural University, Beijing 100193, China. Electronic address: luojj@cau.edu.cn.
  • 4 Department of Nutrition and Health, China Agricultural University, Beijing 100193, China. Electronic address: luo.yongting@cau.edu.cn.
  • 5 Department of Nutrition and Health, China Agricultural University, Beijing 100193, China. Electronic address: zhuyinhua@cau.edu.cn.
PMID: 41175577 DOI: 10.1016/j.phymed.2025.157482
Abstract

Background: Doxorubicin (DOX)-induced cardiotoxicity remains a major clinical challenge in Cancer chemotherapy, with cardiomyocyte senescence as an emerging pathogenic mechanism. Rosmarinic Acid (RA), a polyphenolic compound with demonstrated Anti-aging properties; however, its precise molecular mechanisms in targeting cellular senescence remain to be fully elucidated.

Purpose: This research aimed to explore how RA affects cardiomyocyte senescence and its treatment efficacy in DOX-induced cardiotoxicity.

Study design and methods: In the DOX-induced senescent HL-1 cardiomyocyte model, the anti-senescence effects of RA were assessed by CCK8, Senescence-Associated β-galactosidase (SA-β-gal) staining, RT-qPCR and ELISA. The molecular targets underlying RA's anti-senescence activity were examined by Activity-Based Protein Profiling (ABPP), Cellular Thermal Shift Assay (CETSA), Microscale Thermophoresis (MST), western blot and molecular docking. The therapeutic effect of RA was investigated in the DOX-induced cardiotoxicity mouse model by evaluating survival rate, echocardiographic, heart failure biomarkers, senescence symptoms, histopathology and immunofluorescence analysis.

Results: Through cellular screening of natural polyphenolic compounds, we identified and confirmed RA as an effective inhibitor of DOX-induced cardiomyocyte senescence by decreased SA-β-gal activity, downregulating p16/p21 and attenuating SASP secretion (IL-6, Il-1β, Tnf-α). Mechanistically, RA upregulated 14-3-3θ expression, enhanced FOXO1 phosphorylation, and inhibited its nuclear translocation, thereby attenuating the activation of senescence-associated signaling pathways. In a murine model of DOX-induced cardiotoxicity, RA administration markedly suppressed cardiomyocyte senescence, improved survival rates, maintained cardiac functional parameters, and attenuated key pathological features including myocardial atrophy, fibrotic remodeling, and mitochondrial impairment.

Conclusion: Our findings established RA as a promising therapeutic agent for preventing DOX-induced cardiotoxicity through the modulation of the 14-3-3/FOXO1 signaling axis, offering a novel pharmacological approach to enhance the safety profile of current Cancer chemotherapy.

Keywords

14-3-3 proteins; Cardiotoxicity; Cellular senescence; Doxorubicin; Foxo1; Rosmarinic acid.

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