# Advances in natural compounds modulating autophagy for the therapeutic intervention of heart failure

## TL;DR

This review explores how natural compounds can modulate autophagy to treat heart failure, offering insights into their mechanisms and therapeutic potential.

## Contribution

The paper systematically categorizes natural compounds and integrates their effects on autophagy pathways in heart failure for the first time.

## Key findings

- Natural compounds like flavonoids and polyphenols influence key autophagy pathways such as AMPK/mTOR and SIRT1/FOXO.
- These compounds reduce cardiac hypertrophy and mitochondrial dysfunction by modulating autophagy.
- The review identifies compound-specific differences in autophagy-mediated cardioprotection.

## Abstract

Heart failure (HF) represents the terminal stage of multiple cardiovascular disorders and is characterized by substantial morbidity, disability, and mortality. Although standard pharmacotherapies offer partial symptomatic relief, their capacity to halt or reverse disease progression remains limited. In recent years, autophagy—an essential intracellular degradation and recycling process that safeguards cardiomyocyte homeostasis—has emerged as a critical determinant in the onset and progression of HF. In this review, we systematically examined approximately 170 research articles related to “natural compounds-autophagy-HF” published up to 2025, and synthesized major advances reported over the past five years. Based on chemical structure and natural source, representative bioactive compounds were categorized into five major classes: flavonoids, polyphenols, alkaloids, terpenoids, and marine-derived molecules. We then integrated evidence on the principal autophagy-regulatory signaling cascades influenced by these compounds, including the AMP-activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR) axis, phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), sirtuin 1 (SIRT1)/forkhead box O (FOXO), BCL2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3)/NIP3-like protein X (NIX), and Beclin-1 pathways. Moreover, this review summarizes how these natural compounds modulate autophagy to attenuate key pathological processes associated with HF, including cardiac hypertrophy, adverse ventricular remodeling, mitochondrial dysfunction, and cardiomyocyte apoptosis. By comparing convergent mechanisms and compound-specific differences in autophagy-mediated cardioprotection, we highlight emerging mechanistic patterns and therapeutic implications. Collectively, through structured classification of compounds, integration of autophagy signaling pathways, and assessment of translational potential, this review provides a systematic framework to guide the rational application and further development of natural products for the prevention and treatment of HF.