Polydopamine Nanoparticles-Encapsulated Ferroptosis Inhibitor Ferstatin-1 Promotes GPX4 Expression by Down-Regulating NOX4 to Alleviate Myocardial Ischemia-Reperfusion Injury.

Objective: Polydopamine nanoparticles (PDA NPs) are a promising topic in the fields of drug delivery, tissue engineering, bioimaging, etc. The present study aims to explore the impact of PDA NPs carrying ferroptosis inhibitor ferstatin-1 (Fer-1) on myocardial ischemia-reperfusion injury (MIRI).

Methods: After establishment of a rat model of MIRI and PDA NPs, the rats were divided into 4 groups: model group, sham operation group, Fer-1 group, and nano+Fer-1 group (n=8). To detect the effect of PDA NPs encapsulating Fer-1 on ferroptosis in MIRI rats, we further set up NOX4 overexpression group (pc-NOX4 group), NOX4 inhibitor group (Fulvene-5 group), nano+Fer-1+pc-NOX4 group, and nano+Fer-1+Fulvene-5 group (n=8). A CCK-8 assay was conducted to assess cell viability and staining to detect cardiomyocyte apoptosis and observe myocardial infraction.

Results: PDA NPs loaded with Fer-1 were successfully prepared with good safety and biocompatibility. Administration of PDA NPs carrying Fer-1 notably alleviated myocardial injury and hindered the process of ferroptosis in MIRI rats when inducing downregulation of NOX4 expression. Additionally, overexpression of GPX4 significantly attenuated myocardial injury in MIRI rats. While Fer-1 was shown to inhibit the expression of NOX4, the NOX4 inhibitor Fulvene-5 greatly elevated GPX4 and FTH1 expression in cardiomyocytes, and down-regulated the content of Fe²⁺, especially in the nanometer+Fer-1+Fulvene-5 group.

Conclusion: With promising safety and biocompatibility, PDA NPs encapsulated Fer-1 decrease GPX4 and FTH1 expression by inhibiting the level of NOX4 in myocardial cells of MIRI rats, thereby suppressing ferroptosis of cardiomyocytes and alleviating myocardial injury.