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Targeting Zfp36 to combat cardiac hypertrophy: Insights into ferroptosis pathways
Mingyu Zhang1, Xiaoxiang Guan2, Zheng Dong1
1State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology (State Key Labratoray -Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China.
Insights
Zinc finger protein 36 (Zfp36) mitigates cardiac hypertrophy by inhibiting ferroptosis. It targets Ythdc2 mRNA, preventing glutathione depletion and preserving heart function, offering a new therapeutic avenue.
Area of Science:
- Cardiovascular Biology
- Molecular Mechanisms of Disease
- Cellular Stress Responses
Background:
- Cardiac hypertrophy precedes heart failure, a major cause of mortality.
- The role of Zinc finger protein 36 (Zfp36) in cardiac hypertrophy and ferroptosis is largely unknown.
- Understanding Zfp36's mechanism is crucial for developing new therapies.
Purpose of the Study:
- To investigate the regulatory role of Zfp36 in ferroptosis during cardiac hypertrophy.
- To elucidate the molecular mechanisms by which Zfp36 influences cardiac hypertrophy.
- To identify Zfp36 as a potential therapeutic target.
Main Methods:
- Single-cell sequencing to assess Zfp36 expression in cardiac hypertrophy.
- In vitro studies using cardiomyocytes treated with Angiotensin II (Ang II).
- In vivo studies using a transverse aortic constriction (TAC) model.
- Investigating the interaction between Zfp36, Ythdc2 mRNA, and SLC7A11 mRNA.
Main Results:
- Zfp36 expression is reduced in cardiac hypertrophy.
- Zfp36 inhibits ferroptosis and reduces hypertrophic phenotypes in cardiomyocytes and myocardial tissue.
- Zfp36 binds to Ythdc2 mRNA, promoting its degradation and consequently stabilizing SLC7A11 mRNA and maintaining glutathione (GSH) levels.
- Ferrostatin-1 alleviated hypertrophy in si-Zfp36 treated cells, confirming ferroptosis involvement.
Conclusions:
- Zfp36 attenuates cardiac hypertrophy by inhibiting ferroptosis through the Ythdc2/SLC7A11/GSH pathway.
- This study reveals a novel regulatory pathway for cardiac hypertrophy.
- Zfp36 presents a promising therapeutic target for cardiac hypertrophy and related heart failure.
Background:
Cardiac hypertrophy is a precursor to heart failure and represents a significant global cause of mortality, thereby necessitating timely and effective therapeutic interventions. Zinc finger protein 36 (Zfp36) is recognised as a critical regulator of ferroptosis; however, its role and underlying mechanisms in cardiac hypertrophy remain largely unexplored. This study aims to investigate the regulatory function of Zfp36 in ferroptosis within the context of cardiac hypertrophy.
Methods And Results:
Single-cell sequencing analysis demonstrated a reduction in Zfp36 expression associated with cardiac hypertrophy. Zfp36 was observed to mitigate ferroptosis and reduce hypertrophic phenotypes in cardiomyocytes subjected to Angiotensin II (Ang II) and in myocardial tissues induced by transverse aortic constriction. The ferroptosis inhibitor Ferrostatin-1 was shown to alleviate hypertrophy when co-incubated with si-Zfp36 and Ang II. Mechanistically, Zfp36 binds to the 3' untranslated region (3'UTR) of Ythdc2 mRNA, facilitating its degradation. Ythdc2 subsequently binds to SLC7A11 mRNA, enhancing its decay, which leads to a reduction in glutathione (GSH) levels, thereby exacerbating ferroptosis and cardiac hypertrophy. Furthermore, overexpression of Ythdc2 reversed the protective effects conferred by Zfp36, while silencing of Ythdc2 counteracted the effects of Zfp36 knockdown.
Conclusions:
This study elucidates the role of Zfp36 in cardiac hypertrophy, specifically detailing its modulatory mechanism via the Ythdc2/SLC7A11/GSH ferroptosis pathway. These insights lay the groundwork for innovative approaches to understanding the pathological mechanisms underlying cardiac hypertrophy and enhancing clinical interventions.
Key Points:
Zfp36 was initially demonstrated to attenuate cardiac hypertrophy through the inhibition of ferroptosis in cardiomyocytes, providing a new target for therapeutic strategies targeting ferroptosis. Zfp36 facilitated the degradation of Ythdc2 mRNA by binding to it, subsequently inhibiting Ythdc2-mediated degradation of SLC7A11 mRNA, and maintaining GSH levels. This elucidates a previously unrecognized regulatory pathway in the context of cardiac hypertrophy.
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