Salidroside Alleviates Mobocertinib-Induced Cardiotoxicity by Improving Cardiac Electrophysiology

Area of Science:

• Cardiology
• Pharmacology
• Molecular Biology

Background:

• Mobocertinib, a tyrosine kinase inhibitor for EGFR exon 20 insertion-mutated non-small cell lung cancer, causes cardiotoxicity, notably QT prolongation.
• Salidroside, a natural compound from Rhodiola rosea, possesses known cardioprotective effects.

Purpose of the Study:

• To investigate the electrophysiological mechanisms of mobocertinib-induced cardiotoxicity.
• To evaluate the cardioprotective efficacy of salidroside against mobocertinib toxicity.

Main Methods:

• Langendorff-perfused rat hearts and neonatal rat cardiomyocytes (NRCMs) were used.
• Electrophysiological parameters were mapped using high-resolution multichannel electrophysiology.
• NRCMs underwent transcriptomic sequencing, qRT-PCR, and western blot analysis.

Main Results:

• Mobocertinib dose-dependently prolonged cardiac intervals (PR, JT, QTc), increased conduction heterogeneity, and reduced heart rate.
• Salidroside pretreatment significantly attenuated mobocertinib-induced electrophysiological abnormalities in both isolated hearts and NRCMs.
• Transcriptomic analysis revealed alterations in calcium signaling, aldosterone synthesis, cGMP-PKG, and adrenergic pathways, with differential regulation of Atp2b2 and Agtr1b.

Conclusions:

• Salidroside effectively mitigates mobocertinib-induced cardiotoxicity by normalizing electrophysiological function.
• The protective mechanism involves modulating Atp2b2/Agtr1b-related signaling networks.
• Salidroside presents a potential novel cardioprotective strategy for patients receiving mobocertinib.