Cardiol Res Pract. 2026 Aug 2;2026:8878178. doi: 10.1155/crp/8878178. eCollection 2026.

ABSTRACT

Ferroptosis has recently been identified as a critical mechanism underlying arsenic trioxide (ATO)-induced cardiotoxicity. This study aimed to determine whether Honokiol (HKL) protects against ATO-induced cardiac injury by inhibiting ferroptosis and to investigate the role of the SIRT3 signaling pathway in this process. Using 129S1/SvImJ wild-type (WT) and SIRT3-knockout (SIRT3^-/-) mice, we demonstrated that HKL attenuates ATO-induced myocardial injury and hypertrophy in a SIRT3-dependent manner. Mechanistically, HKL reduced oxidative stress through the SIRT3/SOD2 pathway, as evidenced by decreased mitochondrial ROS production and SOD2 acetylation, along with preserved mitochondrial ATP generation capacity. Furthermore, HKL inhibited ferroptosis, indicated by reduced iron content, MDA levels, and 4-HNE expression, along with restored GPX4 and GSH levels. Notably, HKL restored autophagic flux impaired by ATO, and this effect was associated with its antiferroptotic and cardioprotective actions. Pharmacological or genetic inhibition of SIRT3 or autophagic flux abolished the protective effects of HKL. Autophagic flux is closely associated with the protective effect of Honokiol on ATO-induced ferroptosis. These findings reveal that HKL protects against ATO-induced cardiomyopathy by restoring autophagic flux and inhibiting ferroptosis via the SIRT3 signaling pathway.

PMID:42549032 | PMC:PMC13430285 | DOI:10.1155/crp/8878178