Senescent Schwann cells as therapeutic targets in nerve regeneration and peripheral neuropathies

Peripheral nerve regeneration declines with aging and prolonged denervation, yet the underlying mechanisms have remained elusive. Recent studies identify senescent Schwann cells (senSCs) as a key contributor. Following injury, repair Schwann cells (SCs) enter a senescent state marked by p16^INK4a/p21^CIP1 upregulation and secretion of a senescence-associated secretory phenotype (SASP) that impairs axonal regrowth. Clearing senSCs in preclinical models restores regeneration, suggesting that failed repair results from active inhibition rather than diminished capacity. Moreover, SASP-like signatures emerge across neuropathies of diverse etiology, suggesting broader relevance. In this review, we synthesize emerging evidence linking SC senescence to impaired regeneration and chronic neuropathies and outline therapeutic strategies targeting senescence. We also examine translational challenges and explore how these approaches could advance nerve repair and neuropathy treatment.