BACKGROUND: Heart failure (HF) is a prevalent and critical cardiac condition that leads to profound structural and functional changes in the heart. Although traditional treatments have shown partial efficacy, the long-term outcomes remain suboptimal. Emerging research has highlighted the pivotal role of oxidative stress and ferroptosis in HF progression. This study investigates a new therapeutic approach utilizing antioxidant polyphenol nanoparticles loaded with a STAT3 agonist (PN@Col) to target these pathways and improve age-related HF. RESULTS: Key cells and genes contributing to HF progression were identified via analysis of the GEO database, with single-cell RNA sequencing (scRNA-seq) and AUCell analysis used to evaluate differential gene expression. The STAT3 gene was highlighted as essential, and its functionality was further validated in vitro through cell experiments, confirming its impact on cardiomyocytes (CMs) in HF. Following the development of PN@Col, in vitro experiments showed that PN@Col effectively reduced oxidative stress and ferroptosis in CMs. In vivo studies in elderly HF mice demonstrated significant improvements in cardiac function following PN@Col treatment. CONCLUSIONS: PN@Col offers a promising therapeutic approach to age-related HF by mitigating oxidative stress and ferroptosis in cardiomyocytes. These findings provide a solid scientific foundation for PN@Col as a potential novel treatment strategy for HF, supporting further exploration toward clinical application.