DDHD2 is a diacylglycerol (DAG) and triacylglycerol (TAG) lipase essential for lipid homeostasis in the central nervous system 12. It functions as the principal brain TAG lipase and cooperates with PNPLA2/ATGL in neuronal TAG catabolism 3. DDHD2 exhibits dual enzymatic capacities: it hydrolyzes neutral lipids (preferentially DAG over TAG and phospholipids) and possesses transacylase activity to remodel TAG acyl chains 4. Beyond lipase function, DDHD2 acts as a cargo receptor for lipophagy by binding ATG8 family proteins (LC3, GABARAPs) through two LC3-interacting region motifs, enhancing lipid droplet autophagic clearance 56. DDHD2 also generates saturated free fatty acids critical for synaptic plasticity and memory formation through interaction with STXBP1 7. Mutations in DDHD2 cause spastic paraplegia type 54 (SPG54), an autosomal recessive neurodegenerative disorder characterized by progressive lower limb spasticity and massive lipid droplet accumulation in the brain 85. Loss of DDHD2 impairs neuronal bioenergetics, as neurons require FA β-oxidation from lipid droplets to sustain synaptic ATP production and electrical activity 3. These findings establish DDHD2 as a critical regulator of neuronal lipid metabolism and synaptic function.