MYLK3 encodes cardiac-specific myosin light chain kinase (cMLCK), which plays a crucial role in cardiac contractility through phosphorylation of ventricular myosin regulatory light chain (MYL2) 1. The kinase regulates sarcomere organization and cardiac myofibril assembly, with proper function essential for maintaining normal cardiac contractility 1. Loss-of-function mutations in MYLK3 cause familial dilated cardiomyopathy (DCM), with heterozygous variants leading to reduced protein expression and impaired MYL2 phosphorylation 23. Mechanistically, MYLK3 deficiency increases the ratio of superrelaxed myosin states, contributing to systolic dysfunction 1. The protein is regulated by GATA4-mediated transcription and can be targeted by cardiotoxic drugs like sunitinib and osimertinib, which cause excessive autophagic degradation or transcriptional suppression respectively 45. MYLK3 also functions downstream of calcium/calmodulin signaling, phosphorylating CAMK2 to regulate calcium homeostasis through the PLN-SERCA2a pathway 4. Therapeutic restoration of MYLK3 activity represents a promising myotropic therapy for heart failure, as demonstrated by small molecule activators and gene therapy approaches 1.