Single-cell multi-omics analysis reveals the mechanism of action of a novel antioxidant polyphenol nanoparticle loaded with STAT3 agonist in mediating cardiomyocyte ferroptosis to ameliorate age-related heart failure

• Published in: Journal of nanobiotechnology Vol. 23; no. 1; pp. 258 - 30
• Main Authors: Zheng, Haoyuan, Tian, Yuan, Li, Dongyu, Liang, Yanxiao
• Format: Journal Article
• Language: English
• Published: London BioMed Central 29.03.2025; BioMed Central Ltd; BMC
• Subjects: Agonists (Biochemistry); Animals; Antioxidants; Antioxidants - chemistry; Antioxidants - pharmacology; Biotechnology; Care and treatment; Cell death; Chemistry; Chemistry and Materials Science; Ferroptosis; Ferroptosis - drug effects; Health aspects; Heart failure; Heart Failure - drug therapy; Heart Failure - metabolism; Male; Mice; Mice, Inbred C57BL; Molecular Medicine; Multiomics; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Nanoparticles; Nanoparticles - chemistry; Nanotechnology; Oxidative stress; Oxidative Stress - drug effects; Polyphenol nanoparticles; Polyphenols; Polyphenols - chemistry; Polyphenols - pharmacology; Signal transducer and activator of transcription 3; Single-Cell Analysis; STAT3 Transcription Factor - agonists; STAT3 Transcription Factor - metabolism; Testing; China; Heart failure; Oxidative stress; Ferroptosis; Polyphenol nanoparticles; Signal transducer and activator of transcription 3
• ISSN: 1477-3155; 1477-3155
• DOI: 10.1186/s12951-025-03317-x

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. Graphical Abstract