PARP1 rewires neuroinflammatory and redox metabolism associated with reactive neuroglia in neuropathic pain.

Neuroinflammation, oxidative stress and metabolic dysfunction are co-dependent drivers of neuropathic pain, jointly sustaining reactive gliosis and spinal sensitization. The interplay among neuroinflammation, redox imbalance, and metabolic reprogramming in glial cells represents a crucial process in this context, but the integrative mechanisms involved remain elusive. Poly(ADP-ribose) polymerase 1 (PARP1), a nuclear enzyme activated by genotoxic stress, has emerged as a key regulator of neuroinflammatory-associated diseases. The aim of the present study was to investigate the role of PARP1 in the pathophysiology of neuropathic pain and to evaluate the neuroglia phenotype and metabolism. Using a combination of in vitro glial cell cultures and an in vivo model of peripheral nerve injury, we demonstrated that sustained PARP1 activation triggers parthanatos, apoptosis signalling, and reactive gliosis, promoting neuroinflammation and maladaptive redox-inflammatory coupling in the spinal cord. At the behavioural level, PARP1 inhibition attenuated mechanical allodynia and improved motor coordination in rats with chronic constriction injury (CCI) of the sciatic nerve. Multi-omics profiling revealed a broad restoration of injury-altered proteomic and metabolic signatures, converging on restoring redox imbalance and related metabolic pathways, including glutathione and amino acid metabolic processing. Cell-type-specific knockdown of PARP1 established a causal link between redox balance, mitochondrial metabolism, and intercellular crosstalk during microglia inflammatory priming. Taken together, these findings highlight PARP1 as a functional regulator of the glial cell reactive phenotype in neuropathic pain and support its inhibition as a strategy to modulate central sensitization mechanisms.