# SIRT1 deficiency promotes age-related heart failure through enhancing ferroptosis via GATA4-HADHA-GPX4 axis

## TL;DR

This study shows that SIRT1 deficiency contributes to age-related heart failure by promoting ferroptosis through a specific molecular pathway involving GATA4, HADHA, and GPX4.

## Contribution

The study identifies a novel SIRT1-GATA4-HADHA-GPX4 axis linking SIRT1 deficiency to ferroptosis in age-related heart failure.

## Key findings

- Aged rats show impaired cardiac function and ferroptosis markers like reduced GPX4 and lipid peroxidation.
- SIRT1 overexpression or activation with resveratrol restores HADHA expression and protects against heart failure in aging models.
- HADHA deficiency leads to mitochondrial dysfunction and ferroptosis, which is reversed by ferroptosis inhibitors.

## Abstract

Aging is a major contributor to the escalating prevalence of heart failure (HF). Ferroptosis has been implicated in age-related disorders and cardiovascular diseases. The role of ferroptosis in age-related HF remains unclear. Here, we show that aged rats exhibit impaired cardiac function accompanied by hallmark features of ferroptosis, including reduced glutathione peroxidase 4 (GPX4) expression and excessive lipid peroxidation. Consistently, cardiomyocyte-specific GPX4 knockout mice develop exacerbated cardiac ferroptosis and pronounced cardiac dysfunction. Iron overload further aggravates ferroptotic injury and cardiac dysfunction in aged rats, whereas pharmacological inhibition of ferroptosis markedly alleviates these effects. Conversely, cardiomyocyte-specific overexpression of GPX4 via rAAV9 attenuates ferroptosis and preserves cardiac function in D-galactose–induced aging mice. Proteomic analysis identifies hydroxyacyl-CoA dehydrogenase subunit A (HADHA) as a key protein markedly downregulated in aging hearts, particularly under iron overload. Mechanistically, HADHA deficiency induces mitochondrial dysfunction and excessive reactive oxygen species production, leading to glutathione depletion, GPX4 suppression, and subsequent ferroptosis. Accordingly, cardiomyocyte-specific knockdown of HADHA in young mice recapitulates ferroptosis-associated cardiac remodeling, which is reversed by ferrostatin-1 treatment. Furthermore, we identify SIRT1 (sirtuin 1) as an upstream regulator of HADHA during cardiac aging. Reduced SIRT1 expression in aging hearts suppresses HADHA transcription through inhibition of GATA4. Importantly, both cardiomyocyte-specific SIRT1 overexpression via rAAV9 in D-galactose–induced aging mice and pharmacological SIRT1 activation by resveratrol in aging rats restore HADHA expression, suppress ferroptosis, and protect against HF. Collectively, these findings establish ferroptosis as a critical contributor to age-related HF and identify the SIRT1–GATA4–HADHA axis as a potential therapeutic target.