SYNE3 (spectrin repeat containing nuclear envelope family member 3) encodes nesprin-3, a critical component of the LINC (Linker of Nucleoskeleton and Cytoskeleton) complex that bridges the nuclear envelope and cytoskeleton. 1 The protein functions as a cytoskeleton-nuclear membrane anchor, binding to plectin (PLEC) to tether the nucleus to intermediate filaments and actin filaments, thereby transmitting mechanical forces across the nuclear envelope and regulating nuclear positioning and movement. 2 SYNE3 expression is transcriptionally regulated by the p63 factor and is essential for maintaining proper nuclear architecture and chr14 organization in keratinocytes. 2 In disease contexts, SYNE3 alterations are associated with multiple cancer types. Copy number alterations of SYNE3 as part of a laminin-binding integrin signature correlate with survival outcomes in bladder urothelial carcinoma and cervical cancers. 3 SYNE3 functions as a tumor suppressor, with its expression exhibiting prognostic value across multiple malignancies, possibly through stabilizing nuclear structure, promoting apoptosis, and modulating the tumor microenvironment. 4 Additionally, genome-wide association studies identified SYNE3 as a sex-specific locus associated with carotid intima-media thickness, a marker of subclinical atherosclerosis. 5 At the molecular level, SYNE3 interacts with SUN5 and outer dense fiber proteins to maintain sperm head-tail junction integrity. 6