摘要Neuronal degeneration and inflammation are hallmark features of spinal cord injury that severely hinder functional recovery.As key regulators of the post-injury microenvironment,macrophages can promote either tissue repair or exacerbate damage.Among macrophage secreted factors,transforming growth factor-beta 1 has emerged as a critical mediator of pathological changes.In this study,we show the pivotal role of macrophage-derived transforming growth factor-beta 1 in driving neuronal senescence and impairing functional recovery after spinal cord injury.In a mouse spinal cord injury model,transforming growth factor-beta 1 levels were significantly increased at the injury site,accompanied by increased mothers against decapentaplegic homolog 2(SMAD2)phosphorylation and upregulation of neuronal senescence markers such as p16INK4a and β-galactosidase activity.Treatment with LY-364947,a SMAD2 phosphorylation inhibitor,markedly reduced the number of senescent neurons,mitigated tissue degeneration,and improved motor function recovery.Additionally,macrophage depletion using clodronate liposomes lowered transforming growth factor-beta 1 levels at the injury site and attenuated neuronal senescence.These findings highlight the transforming growth factor-beta 1-SMAD2 signaling axis as a potential therapeutic target to reduce neuronal senescence and enhance functional recovery following spinal cord injury.