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
  • 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: [email protected].
  • 4. Department of Nutrition and Health, China Agricultural University, Beijing 100193, China. Electronic address: [email protected].
  • 5. Department of Nutrition and Health, China Agricultural University, Beijing 100193, China. Electronic address: [email protected].
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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