Hydrogen nanobubbles effectively reverse doxorubicin-induced myocardial injury by reducing oxidative stress and myocardial fibrosis through dual suppression of the PI3K/AKT and TGF-β/SMAD signaling pathways. The nanoparticle delivery system demonstrates excellent biosafety and myocardial targeting, with significant improvements in cardiac function and echocardiographic parameters in a mouse cardiomyopathy model. This novel hydrogen-based therapeutic approach offers promising potential for treating chemotherapy-induced cardiotoxicity, a major clinical limitation in cancer treatment.
Plain-Language Summary
Researchers created tiny hydrogen-filled particles (about 265 nanometers in size) and tested whether they could protect heart cells from damage caused by doxorubicin, a common chemotherapy drug. In laboratory and mouse studies, these hydrogen nanobubbles reduced harmful molecules called free radicals in heart cells, prevented cell death, and reduced scarring of heart tissue—all while showing good safety. The treatment appeared to work by turning on the heart's natural defense systems and blocking two specific damage pathways in cells.
Abstract
The most severe side effect of chemotherapy is cardiotoxicity, frequently causing myocardial injury characterized by excessive oxidative stress and fibrosis for which effective treatments are lacking. To address this, a hydrogen delivery system, hydrogen nanobubbles (HNBs), was constructed, leveraging hydrogen's selective antioxidant and antifibrotic properties to counteract doxorubicin (Dox)-induced myocardial injury and explore its mechanism. HNBs were constructed via polymer self-assembly. Nanoparticle tracking analysis indicated a size of 265.1 ± 26 nm. The average hydrogen content of HNBs measured by chemical titration was about 1.9 mg/L. TEM revealed spherical HNBs with a dense outer lipid polymer layer encapsulating hydrogen. CCK-8 assays confirmed over 90% cell viability, demonstrating good biosafety. ROS fluorescence staining and flow cytometry showed that HNBs significantly reduced Dox-induced ROS increases. RT-qPCR revealed the upregulation of antioxidant genes (NRF2, SOD2, and GPX-1). Flow cytometry and JC-1 staining indicated that HNBs mitigated apoptosis and restored mitochondrial membrane potential. TEM displayed reduced mitochondrial damage and intracellular vacuolation. In a Dox-induced cardiomyopathy mouse model, HNBs improved cardiac function, normalized echocardiographic parameters (EF, FS, LVIDs, and LVIDd), and lowered myocardial ROS levels. Ultrasonic enhanced images showed that HNBs have good myocardial differential targeting. In vivo fluorescence imaging of mice showed that HNBs could accumulate in the myocardium in large quantities at 1 h. mRNA-seq and network pharmacology suggested that HNBs inhibit myocardial fibrosis. Masson staining results showed that HNBs could improve Dox-induced myocardial fibrosis. RT-qPCR and Western blotting confirmed the reduced expression of fibrosis markers (ACTA2, COL1, and FN1), preliminarily linking the mechanism to suppression of both PI3K/AKT and TGF-β/SMAD pathways. In summary, HNBs inhibit oxidative stress and myocardial fibrosis, reversing Dox-induced cardiac injury primarily through the dual suppression of the PI3K/AKT and TGF-β/SMAD pathways.
