Lactate-mediated Ran lactylation at lysine 123 promotes astrocytes polarization after oxygen-glucose deprivation/reoxygenation

Ischemia and hypoxia near the injury site following spinal cord injury (SCI) lead to early lactate accumulation. Reactive astrocytes polarize and migrate to the lesion site, sealing it off and restricting immune cell infiltration. However, the specific mechanisms through which lactate influences astrocyte polarization remain poorly understood. In this study, we found that lactate can promote astrocyte proliferation, migration and differentiation into A2 after oxygen-glucose deprivation/reoxygenation (OGD/R). Inhibiting signal transducer and activator of transcription 3 (STAT3) nuclear transport reversed lactate-driven astrocyte polarization both in vivo and in vitro. Moreover, lactylome analysis identified nonhistone protein Ran as a target of lactylation at lysine 123 (K123). Ran silencing or mutation at K123 reversed the effects of lactate on STAT3 nuclear transport and astrocyte polarization. We also found that Ran lactylation is regulated by SIRT1. Taken together, our results show that lactate promotes astrocyte polarization via Ran lactylation-dependent regulation of STAT3 nuclear transport.