EFHD1 (EF-hand domain family member D1) is a calcium-binding protein that functions primarily as a mitochondrial calcium sensor regulating cellular metabolism and survival pathways. EFHD1 localizes to the mitochondrial intermembrane space where it acts as a calcium sensor and interacts with key mitochondrial proteins 1. The protein directly binds to mitochondrial calcium uniporter channel (MCUC) subunits including MCU, EMRE, and MCUB, exerting a MICU1-dependent inhibitory effect on mitochondrial calcium uptake 2. In renal cell carcinoma, EFHD1 physically interacts with MCU through its N-terminal domain, suppressing mitochondrial calcium uptake and deactivating the Hippo/YAP signaling pathway to inhibit tumor metastasis 3. EFHD1 also binds to adenine nucleotide translocase-3 (ANT3), inhibiting mitochondrial membrane permeability transition pore opening and promoting cell survival in osteosarcoma 4. Clinically, EFHD1 shows promise as a biomarker, with hypermethylation detected in colorectal cancer plasma samples providing high sensitivity (90%) and specificity (96%) for early-stage detection 5. Decreased EFHD1 expression is associated with diabetic nephropathy progression and correlates with immune cell infiltration patterns 6, while reduced expression in atherosclerotic plaques links to mitochondrial dysfunction and aging-related pathways 7.