What question did this study set out to answer?

The aim is to investigate betulin's therapeutic potential and mechanisms in protecting against pathological cardiac hypertrophy.

March 12, 2026

Betulin Protects Against Cardiac Hypertrophy by Improving AMPK /Nrf2‐Dependent Mitochondrial Function

Key Result

Betulin reduced cardiac hypertrophy and fibrosis by 65%, improved ejection fraction by 13.8% and fraction shortening by 11.6%, via the AMPK/Nrf2 pathway in PCH mice.

Key Points

The aim is to investigate betulin's therapeutic potential and mechanisms in protecting against pathological cardiac hypertrophy.
Induced PCH in C57BL/6J mice using Ang II and aortic constriction.
Administered betulin in the last two weeks of the intervention.
Evaluated cardiac function with echocardiography and molecular techniques.
Utilized RNA sequencing, histological staining, and molecular docking analyses.
Employed AMPK/Nrf2 pathway modulation using inhibitors and genetic knockouts.
Betulin significantly reduced cardiac hypertrophy and fibrosis, with fibrotic area reduced by 65%.
Ejection fraction (EF) increased by 13.8% and fractional shortening (FS) by 11.6%.
Activated AMPK phosphorylation and enhanced Nrf2 nuclear translocation.
Restored mitochondrial function in hypertrophied hearts and cardiomyocytes.
Beneficial effects reversed by AMPK inhibition and abolished in AMPKα2-/- mice.

Structured PICO

Does betulin improve cardiac hypertrophy and mitochondrial function in mouse models of pathological cardiac hypertrophy?

Population

C57BL/6J mice with pathological cardiac hypertrophy induced via angiotensin II infusion and transverse aortic constriction, AMPKα2-/- mice, and Ang II-stimulated cardiomyocytes.

Intervention

Betulin administered in the last 2 weeks.

Comparator

Control/vehicle (PCH mice without betulin treatment).

Outcome

Cardiac function (EF, FS), myocardial injury, remodeling (fibrosis), and mitochondrial function.surrogate

Betulin protects against pathological cardiac hypertrophy and improves mitochondrial function via the AMPK/Nrf2 signaling pathway in preclinical models.

Main Result

Absolute Event Rate: 0% vs 0%

Abstract

Pathological cardiac hypertrophy (PCH) drives heart failure and affects global mortality, without specific pharmacotherapy. Betulin is a natural pentacyclic triterpene exhibiting diverse pharmacological properties. We investigated the therapeutic potential and underlying mechanisms of betulin in PCH. PCH was induced in C57BL/6J mice via angiotensin II (Ang II) infusion and transverse aortic constriction, with betulin administered in the last 2 weeks. Cardiac function was evaluated using echocardiography, and myocardial injury and remodeling were assessed using histological staining and molecular analyses. RNA sequencing and biochemical analyses elucidated molecular mechanisms. Molecular docking (MD) and molecular dynamics simulations (MDS) analyses predicted potential binding modes of betulin with AMP-activated protein kinase (AMPK) and nuclear factor erythroid 2-related factor 2 (Nrf2). To confirm AMPK/Nrf2 pathway-dependent mitoprotective and cardioprotective effects of betulin, the AMPKα2-/- mice, AMPK inhibitor, siNrf2, and AMPK agonist intervention were used. Betulin treatment significantly ameliorated cardiac hypertrophy, fibrosis (reducing fibrotic area by 65%), and dysfunction (increasing EF by 13.8% and FS by 11.6%) in PCH mice. Transcriptomic and biochemical analyses revealed that betulin activated AMPK phosphorylation, promoted Nrf2 nuclear translocation, and upregulated antioxidant genes, restoring mitochondrial function in hypertrophied hearts and Ang II-stimulated cardiomyocytes. MD and MDS analyses indicated that betulin enhanced interactions between AMPK and Nrf2. AMPK inhibition significantly reversed betulin-mediated alleviation of mitochondrial dysfunction by the AMPK/Nrf2 signaling axis. Cardioprotective effects of betulin were abolished in AMPKα2-/- mice and Nrf2-deficient cardiomyocytes. Betulin ameliorates pressure overload-induced PCH and mitochondrial dysfunction by activating AMPK/Nrf2 signaling pathway, highlighting it as a therapeutic agent for PCH.

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