TMEM43 (transmembrane protein 43) is a membrane-spanning protein that plays critical roles in cardiac function, nuclear envelope maintenance, and cellular signaling. The protein primarily localizes to the endoplasmic reticulum and nuclear membranes, where it maintains nuclear envelope structure and is stabilized through interactions with squalene synthase 1. TMEM43 functions as a key regulator of lipid metabolism by suppressing sterol regulatory element-binding proteins (SREBPs) through sequestration of the transcriptional coactivator LRPPRC to the nuclear membrane, thereby controlling adipocyte versus cardiomyocyte differentiation 1. The protein also interacts with mitochondrial voltage-dependent anion channels (VDAC1 and VDAC2), which is crucial for maintaining mitochondrial function 2. Mutations in TMEM43, particularly the S358L variant, cause arrhythmogenic right ventricular cardiomyopathy type 5 (ARVC5), the most aggressive form of ARVC 34. This mutation leads to reduced VDAC binding and mitochondrial dysfunction 2, as well as pro-arrhythmogenic phenotypes with elevated contraction rates and altered calcium handling in cardiomyocytes 5. ARVC5 is characterized by fibrofatty replacement of myocardium, heart failure, and sudden cardiac death, with the disease being particularly severe in males 5. Recent therapeutic approaches using adeno-associated virus-mediated delivery of wild-type TMEM43 show promise for treating this lethal condition 4.