Neurodegenerative diseases are one of the biggest health problems worldwide, but there are no effective disease-modifying therapies available, due to the lack of understanding of the molecular mechanisms involved in chronic neuroinflammation and progressive neuronal loss. There is growing evidence that innate immune dysregulation plays a central role in disease progression, but the role of nucleotide-binding oligomerization domain 1 (NOD1), an intracellular pattern-recognition receptor (PRR), has been understudied. Beyond antimicrobial defense, NOD1 regulates receptor-interacting protein kinase 2 (RIPK2)-dependent nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling and may contribute to neuroinflammatory responses. This review summarizes the structural biology, activation mechanisms, intracellular signaling pathways, and emerging role of NOD1 in neuroinflammation and neurodegenerative diseases. The interaction between NOD1 signaling, the gut-brain axis, and peripheral immune regulation is also discussed, with a focus on how chronic activation of the NOD1-RIPK2 signaling pathway may exacerbate neuroinflammatory responses and influence disease progression. Recent advances in the pharmacological modulation of NOD1, current knowledge gaps, and challenges for clinical translation are also discussed. Altogether, current evidence positions NOD1 as a potential modulator of neuroinflammation and a possible link between innate immune signaling and neurodegeneration, although its role as a primary disease driver remains unestablished. Understanding NOD1-dependent signaling networks may enable targeted immunomodulatory therapies to reduce neuroinflammation and slow neurodegeneration.
