<p>Caspase-6 (Casp6) and Death Receptor 6 (DR6) are critical mediators of programmed cell death and axonal degeneration. Casp6 is activated via the cleavage of disease specific key substrates including tau, huntingtin, α-Synuclein, Prp^Sc and lamin proteins leading to cytoskeletal destabilization, impaired axonal transport, mitochondrial dysfunction, and synaptic loss. DR6 is upstream to Casp6 and it is activated by the N-terminal fragment of amyloid precursor protein (N-APP). DR6 triggers Caspase-6-dependent axonal self-destruction and neuronal apoptosis. This DR6–Casp6 signaling cascade integrates apoptotic and axon degenerative pathways, bridging developmental pruning mechanisms with pathological neurodegeneration. Emerging evidence also implicates DR6 in Wallerian-like axonal degeneration and neuroinflammation via JNK and caspase signaling. The intricate crosstalk between DR6 activation and Casp6 effector function suggests a convergent mechanism underlying neuronal vulnerability and progressive loss in neurodegenerative disorders. Understanding the molecular interplay between DR6 and Casp6 provides valuable insights into early pathogenic events and identifies potential therapeutic targets for halting or reversing neuronal degeneration.</p>