EFHD2 encodes a calcium-binding protein containing EF-hand domains that functions as a critical regulator of inflammation, membrane receptor trafficking, and cellular responses across multiple tissue types. In immune cells, EFHD2 facilitates interferon-γ signaling by interacting with YWHAZ (14-3-3ζ) to promote IFNγR2 translocation to the plasma membrane, thereby mediating inflammatory responses in hepatic macrophages during non-alcoholic steatohepatitis 1. In intestinal epithelial cells, EFHD2 protects against TNF-induced apoptosis by interacting with Cofilin to suppress its phosphorylation, which blocks TNFR1 internalization and prevents cell death 2. EFHD2 also serves as a cargo-specific adaptor for clathrin-independent endocytosis, coupling active Rab21-associated integrins with endocytic machinery components including Arf1 and IRSp53, supporting cancer cell migration and invasion 3. In the nervous system, EFHD2 functions in synaptic plasticity and actin remodeling, with downregulation associated with neurodegenerative processes and dementia 4. Clinical relevance includes associations with schizophrenia susceptibility 5, serving as a prognostic marker in breast cancer 6, and representing a potential therapeutic target for NASH treatment 1.