EFhd2, also known as Swiprosin-1, is a Ca2+ sensor and binding protein [3,4]. It is involved in multiple biological processes including calcium signaling, apoptosis, and actin cytoskeleton regulation. In the immune system, it has immunomodulatory effects, and in the nervous system, it may be associated with synaptic plasticity and neurodegenerative processes [3,5]. Genetic models, such as knockout (KO) mice, are valuable for studying its functions.

In non-alcoholic steatohepatitis (NASH), deletion of EFHD2, either globally or specifically in myeloid cells, improved hepatic steatosis, reduced immune cell infiltration, inhibited lipid peroxidation-induced ferroptosis, and attenuated fibrosis. It also hindered the development of NASH-related hepatocellular carcinoma. Mechanistically, EFHD2 in myeloid cells interacts with YWHAZ, facilitating IFNγR2 translocation and mediating interferon-γ signaling [1]. In intestinal epithelial cells, Efhd2-deficient mice exhibited excessive cell death and exacerbated experimental colitis as EFHD2 protects the intestinal epithelium from TNF-induced apoptosis by blocking TNFR1 internalization [2]. In early sepsis, Efhd2-deficient CD4+ T cells showed impaired T cell receptor-induced Th1 and Th17 differentiation, and reduced levels of phospho-LCK and phospho-ZAP70 [6].

In conclusion, EFHD2 plays crucial roles in the immune response, intestinal inflammation, and NASH. KO mouse models have revealed its significant impact on these disease-related processes, highlighting its potential as a therapeutic target in NASH, intestinal inflammatory diseases, and sepsis-related immune dysregulation.