CFL2 (cofilin 2) is a muscle-specific actin-binding protein encoded on chromosome 14 that controls reversible actin polymerization and depolymerization in a pH-sensitive manner 1. CFL2 binds G- and F-actin in a 1:1 ratio and is the major component of intranuclear and cytoplasmic actin rods, with its F-actin depolymerization activity regulated by association with CSPR3 1. The protein exists as differentially spliced transcripts (CFL2a and CFL2b), with CFL2b predominantly expressed in skeletal muscle and heart 1. Mechanistically, CFL2 regulates myogenic differentiation by controlling actin filament dynamics and modulating myogenic transcription factors (MyoD, MyoG, and MEF2C) 2. During muscle regeneration, dephosphorylated CFL2 becomes the major isoform at later stages 1. CFL2 mutations cause nemaline myopathy 7 and other congenital myopathies including myofibrillar myopathy 3. The human p.A35T mutation results in alternative splicing defects and severe myopathy with sarcomeric disruption and actin accumulations 3. Beyond muscle disease, CFL2 was identified as a susceptibility locus for atrial fibrillation in large genome-wide association studies 4 and Takayasu arteritis 5, suggesting roles in cardiac structural integrity and inflammatory responses. Recent evidence indicates CFL2 contributes to high glucose-induced retinal pigment epithelial cell injury through the AMPK/mTOR pathway 6.