Decoding the regulatory role of ATP synthase inhibitory factor 1 (ATPIF1) in Wallerian degeneration and peripheral nerve regeneration

ATP synthase inhibitory factor 1 (ATPIF1), a key modulator of ATP synthase complex activity, has been implicated in various physiological and pathological processes. While its role is established in conditions such as hypoxia, ischemia‐reperfusion injury, apoptosis, and cancer, its involvement remains elusive in peripheral nerve regeneration. Leveraging ATPIF1 knockout transgenic mice, this study reveals that the absence of ATPIF1 impedes neural structural reconstruction, leading to delayed sensory and functional recovery. RNA‐sequencing unveils a significant attenuation in immune responses following peripheral nerve injury, which attributes to the CCR2/CCL2 signaling axis and results in decreased macrophage infiltration and activation. Importantly, macrophages, not Schwann cells, are identified as key contributors to the delayed Wallerian degeneration in ATPIF1 knockout mice, and affect the overall outcome of peripheral nerve regeneration. These results shed light on the translational potential of ATPIF1 for improving peripheral nerve regeneration. This study aims to understand ATP synthase inhibitory factor 1's (ATPIF1's) role in peripheral nerve regeneration (PNR) using a murine model of sciatic nerve crush injury. Histological exams and behavior assessments revealed ATPIF1 absence hindered nerve tissue reconstruction, delaying sensory and functional recovery. RNA‐sequencing showed reduced immune responses in ATPIF1 knockout mice, particularly CCR2/CCL2 signaling‐mediated macrophage infiltration, slowing Wallerian degeneration and impeding axonal regeneration.