PLEKHM3 (pleckstrin homology domain containing M3) is a scaffold protein primarily involved in skeletal muscle differentiation, where it functions as an AKT1 binding partner. The gene localizes to the cytoplasm and Golgi apparatus during myoblast differentiation. In cardiac pathophysiology, PLEKHM3 serves as a critical target of miR-320 in cardiomyocytes 1. miR-320-mediated PLEKHM3 suppression exacerbates cardiac dysfunction and hypertrophy, while PLEKHM3 re-expression reverses these pathogenic effects. Additionally, PLEKHM3 appears involved in hematological toxicity mechanisms; low-level lead exposure increases hemoglobin levels partly through a PLEKHM3-dependent pathway that influences oxidative DNA damage 2. Clinically, PLEKHM3 has emerged as a cancer-relevant gene. A circular RNA transcript (circ-PLEKHM3) acts as a competing endogenous RNA, sponging miR-320a to upregulate SMG1 in ovarian cancer 3. Circ-PLEKHM3 overexpression enhances curcumin's anti-proliferative and pro-apoptotic effects. Furthermore, PLEKHM3 was identified as a potential diagnostic biomarker for breast cancer subtype stratification 4. These findings suggest PLEKHM3 functions beyond muscle biology, playing roles in cardiac homeostasis, environmental toxicology, and cancer progression, primarily through miRNA-mediated regulation.