DDHD1 is a phospholipase A1 that cleaves ester bonds at the sn-1 position of glycerophospholipids, preferentially hydrolyzing phosphatidate but also acting on phosphatidylinositol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and phosphatidylglycerol. The enzyme regulates polyunsaturated phosphoinositide and phosphatidylserine content in the nervous system, with downstream effects on phosphoinositide signaling molecules critical for cell biology. DDHD1 also modulates mitochondrial morphology, likely through phosphatidate hydrolysis at the mitochondrial surface, and may influence spermatogenesis. DDHD1 dysfunction causes hereditary spastic paraplegia types 28 and 56, neurodegenerative disorders characterized by lower-limb spasticity and axonal degeneration. Loss-of-function mutations in DDHD1 result in accumulation of oleic acid-containing phosphatidylinositol species, suggesting altered phospholipid metabolism as a disease mechanism 1. Phosphorylation by CDK1/cyclin A2 and CDK5/p35 alters DDHD1 subcellular localization without substantially affecting catalytic activity 2. Beyond neurological disease, DDHD1 supports colorectal cancer cell proliferation and survival; downregulation reduces viability and increases apoptosis in cancer cells 3. Tumor invasion depth correlates with DDHD1 expression in colorectal cancer tissues 4. Recent evidence suggests DDHD1 regulates cardiac calcium homeostasis in obesity through lysophosphatidylinositol signaling 5, indicating broader metabolic roles beyond the nervous system.