Temporal and demographic patterns of peripheral nerve proteomes in preclinical neuropathic pain

Peripheral nerves drive movement and sensation but are highly vulnerable to injury, making them critical sites in the development of neuropathic pain. Nerve trauma initiates profound plasticity, yet the molecular programs driving both early and persistent axonal remodeling remain poorly understood. Here, we present a uniquely longitudinal proteomic perspective on injured sciatic nerve fibers, spanning acute (7-14 days) to chronic (98 days) stages in the mouse spared nerve injury (SNI)-model of neuropathic pain. Given the importance of demographic diversity in pain research, we compared male and female mice at adolescent and adult stages. Using MEFISTO (MEssage FInding for Spatio-Temporal Ordering), a time-aware latent factor model, we resolved complex proteome trajectories and identified temporal patterns of injury-induced axonal reorganization. Notably, we observed sex- and age-biased differences in immune and neuronal pathways. Despite comparable pain behaviors, these molecular distinctions suggest heterogeneity of nerve injury-induced molecular changes. In parallel, a robust sex-shared injury response emerged, characterized by early neuronal injury/repair, sustained metabolic and immune reprogramming and late structural and transcriptional remodeling. Many dozens of identified proteome alterations match transcriptome changes in nerves from human patients with neuropathy highlighting the translational relevance of our data. In summary, we provide a demographically inclusive, temporally resolved resource that advances our understanding of long-term peripheral nerve remodeling. By bridging early and late injury phases our findings provide a framework for mechanistic translational research and identifying therapeutic targets relevant to nerve injury and associated neuropathic pain.