RPS3‐Enriched Extracellular Vesicles Mediate Liver‐Spinal Cord Inter‐Organ Communication

Spinal cord injury (SCI) induces bidirectional inter-organ communication via extracellular vesicles (EVs) with multiple peripheral organs. Here, we identify the liver as a critical regulator that inhibits endogenous neuronal repair. Proteomics of plasma EVs from SCI patients and RNA-sequence of post-injury livers revealed a rapid increase of ribosomal protein S3 (RPS3) in plasma EVs and liver-derived EVs (LEVs). These RPS3-enriched LEVs are transported to the spinal cord lesion sites, where they are taken up by neural stem cells (NSCs) and astrocytes. Mechanistically, RPS3 activates nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling in recipient cells, inhibiting NSC differentiation into neurons and oligodendrocytes and polarizing astrocytes toward a neuroinflammatory phenotype. Further detection identified activated Kupffer cells (KCs) as the primary source of RPS3, initiating an intra-hepatic cascade that further amplified RPS3 expression in hepatocytes. Crucially, in vivo depletion of KCs or hepatic RPS3 effectively attenuated NF-κB activation, restored axonal regeneration and remyelination, and promoted neurological functional recovery. This work highlights a liver-spinal cord axis wherein RPS3-enriched hepatic KC-derived EVs impair central nervous system (CNS) regeneration via the NF-κB activation, presenting a promising prognostic biomarker and novel therapeutic target for SCI.