Macrophage STING signaling as a conserved inhibitor for axonal regeneration with aging: insights from comparative human-mouse transcriptomics

Peripheral nerve regeneration declines with aging, leading to poor functional recovery after injury. However, whether the underlying molecular mechanisms are conserved between humans and mice remains unclear. Understanding these conserved processes is critical for translating preclinical findings into clinical strategies for nerve repair. Sciatic nerve tissues were collected from young and aged human donors and mice for bulk RNA sequencing. Cross-species transcriptomic analyses were performed to identify conserved age-associated gene expression changes. Immunofluorescence and Western blot analyses were used to assess STING pathway activation in macrophages within aged nerves. To determine the functional role of this pathway, aged mice received pharmacological STING inhibition starting four weeks before injury, with post-injury dosing duration tailored to each experimental endpoint. In vitro co-culture assays were conducted to evaluate the effect of macrophage STING activation on axonal outgrowth in human motor ganglion sensory neurons. We identified 14,855 one-to-one orthologous gene pairs with broadly conserved expression patterns between humans and mice. Among age-associated pathways, macrophage STING signaling was consistently activated in aged sciatic nerves across both species. Enhanced STING pathway activity was confirmed at the protein level. Inhibition of STING in aged mice significantly improved axonal regeneration and remyelination following nerve injury. Conversely, activation of STING in macrophages suppressed axonal outgrowth in both human-derived and mouse neurons. This study identifies macrophage STING signaling as a conserved and potent inhibitor of axonal regeneration during aging. Targeting this pathway may represent a promising therapeutic approach to enhance peripheral nerve repair and restore regenerative capacity in older individuals.