Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder characterized by selective motor neuron degeneration driven by intersecting pathological processes, including impaired proteostasis, defective autophagy, oxidative stress, excitotoxicity, and chronic neuroinflammation. A key axis involves the pathological interplay between autophagy-deficient neurons and reactive glial cells, involving astrocyte-derived microRNAs such as miR-155 that suppress neuronal ATG5 expression, and microglial cytokines inhibit the ULK1/FOXO1 complex, collectively impairing autophagosome initiation. Concurrently, elevated neuronal reactive oxygen species oxidize ATG4B, disrupting autophagosome lysosome fusion and exacerbating intracellular toxic substrate accumulation. Damaged neurons release mitochondrial DNA, cathepsins, and CX3CL1, further activating glial cells and perpetuating a self-reinforcing cycle of neurotoxicity. These intercellular interactions contribute to progressive motor neuron vulnerability and highlight the central role of autophagy neuroinflammation crosstalk in amyotrophic lateral sclerosis pathogenesis. Although challenges such as limited central nervous system drug penetration and insufficient biomarkers remain, therapeutic strategies targeting this axis using gene therapy, nanocarriers, engineered exosomes, and optogenetic tools offer potential to restore cellular homeostasis and mitigate disease progression.