Targeting the NAD+-PARP1-XRCC1 axis in ALS.

Amyotrophic lateral sclerosis (ALS) remains a fatal neurodegenerative disease with few effective therapies. Emerging evidence indicates that oxidative DNA damage, defective base excision and single-strand break repair, and progressive NAD+ depletion contribute to motor neuron degeneration. The NAD+-PARP1-XRCC1 axis sits at the intersection of genome maintenance and metabolic control, linking DNA damage signaling to cellular bioenergetics. When dysregulated, this pathway may drive persistent PARP1 activation, failed repair, and energetic collapse. In this review, we integrate mechanistic and translational evidence supporting this axis as a therapeutic target in ALS. We propose a staged translational framework that prioritizes repurposable low-trapping PARP1 inhibitors combined with NAD+ support, followed by central nervous system-directed RNA-lipid nanoparticle delivery of repair factors, with poly(ADP-ribose) and NAD+ metabolites as pharmacodynamic biomarkers.