TAK1 Impedes Peripheral Nerve Regeneration After Injury by Evoking Sustained Inflammation

Peripheral nerve injury (PNI) often leads to severe functional deficits, yet the molecular mechanisms underlying nerve regeneration remain incompletely understood. Here, the function of transforming growth factor-β-activated kinase 1 (TAK1) in peripheral nerve regeneration was examined using murine and rat models of sciatic nerve injury. The results show that TAK1 overexpression impairs nerve regeneration and functional recovery, whereas pharmacological inhibition of TAK1 with Takinib promotes these processes. Mechanistically, the detrimental effects of TAK1 are associated with sustained inflammatory responses within the sciatic nerve. TAK1 is predominantly expressed in Schwann cells and fibroblasts in the sciatic nerve, where it activates NF-κB signaling. Specifically, TAK1 phosphorylates protein phosphatase 1 regulatory subunit 18 (PPP1R18) at serine 213, thereby relieving its suppression on the NF-κB pathway and facilitating the nuclear accumulation of NF-κB p65. This activation drives chemokine expression, leading to enhanced recruitment of M1 macrophages and the establishment of a proinflammatory microenvironment that impedes remyelination and nerve regeneration. Collectively, these findings identify TAK1 as a critical negative regulator of peripheral nerve repair and highlight TAK1 inhibition as a potential therapeutic approach for improving recovery following PNI.