TMEM43, also known as LUMA, is a ubiquitously expressed transmembrane protein with phylogenetically high conservation [6]. It has been implicated in multiple biological functions and disease conditions. TMEM43 is associated with pathways related to cardiac function, metabolism, and is involved in diseases such as arrhythmogenic right ventricular dysplasia/cardiomyopathy, Emery-Dreifuss muscular dystrophy, and various cancers [2,3,4,7]. Genetic models, like mouse models, have been crucial in understanding its functions.

In mice, TMEM43 knockdown in hearts deteriorated lipopolysaccharide (LPS)-induced cardiac injury and dysfunction, while overexpression alleviated these effects by inhibiting ferroptosis, suggesting its protective role in sepsis-induced cardiac injury [1]. The TMEM43 S358L mutation in knock-in mouse models led to systolic dysfunction, arrhythmias, fibro-fatty infiltration in the heart, along with abnormal intestinal phenotypes such as elongated villi and fatty infiltration, indicating its importance in maintaining cardiac and intestinal homeostasis [3]. In zebrafish, overexpression of WT and mutant TMEM43 variants led to cardiac morphological and ultrastructural defects, and Nuclease technology mutants showed age-dependent heart enlargement [5].

In conclusion, TMEM43 plays essential roles in maintaining cardiac and intestinal homeostasis, and inhibiting ferroptosis in the context of sepsis-induced cardiac injury. Studies using KO/CKO mouse models and other genetic models have significantly contributed to understanding its functions in arrhythmogenic cardiomyopathy and related cardiac and metabolic diseases, providing insights into potential therapeutic strategies for these conditions.