This mechanistic study combines a mouse model with rodent and human cardiomyocyte platforms to characterize trametinib cardiotoxicity. Mice developed contractile dysfunction within three days and heart failure within two weeks. Trametinib impaired mitochondrial respiration and electron-transport activity, promoted release of mitochondrial danger signals including mtDNA, and activated innate immune pathways such as cGAS-STING. A phosphomimetic STAT3-S727 construct reversed the respiratory lesion in cell models.
Key findings
- Contractile dysfunction appeared by day three and heart failure by two weeks in mice. • Trametinib impaired oxidative metabolism and electron-transport activity. • Mitochondrial damage was linked to mtDNA release and cGAS-STING activation.
Why this matters globally
The findings identify a mechanistic route that may inform monitoring or cardioprotection during MEK inhibition, but they do not yet show that targeting this pathway prevents heart failure in patients.
Thai researcher contribution
Researchers linked to Navamindradhiraj University, Vajira Hospital and Chiang Mai University contribute to the cardio-oncology collaboration.
Limitations to consider
Most evidence is preclinical. Dose, exposure and model susceptibility may not mirror patients with comorbidities, so clinical validation is required.