ARL6IP1 (ADP-ribosylation factor-like 6 interacting protein 1) is a multifunctional endoplasmic reticulum (ER) membrane protein that plays critical roles in ER organization, autophagy regulation, and cellular survival. The protein positively regulates glutamate transport by enhancing SLC1A1/EAAC1-mediated glutamate uptake through increased glutamate affinity in a protein kinase C-dependent manner, likely by reducing interaction with the negative regulator ARL6IP5 1. ARL6IP1 is essential for ER tubular network formation and maintenance, forming heteromeric clusters with FAM134B that drive reticulophagy (selective ER autophagy) 2. Ubiquitination of ARL6IP1 promotes this reticulophagy process, which is crucial for neuronal maintenance 2. The protein also negatively regulates apoptosis by modulating caspase-9 activity and serves as an mRNA target of HuD, contributing to tumor cell survival under stress conditions 3. Mutations in ARL6IP1 cause hereditary spastic paraplegia 61 (SPG61), an autosomal recessive neurodegenerative disorder characterized by motor neuron degeneration 4. Disease mechanisms involve disrupted lipid homeostasis and ER organization in long motor neuron axons, with liver X receptor agonists showing therapeutic potential 4. ARL6IP1 is also implicated in cancer progression, particularly breast cancer, where it regulates glycolysis and cellular behavior 5.