Astrocytic LMP2 Coordinates NF‐κB and TGF‐β1/Smad3 Signaling to Drive Neuroinflammation after Cerebral Ischemia/Reperfusion

Astrocyte reactivity critically shapes neuroinflammatory outcomes after ischemic stroke, yet the upstream regulators governing astrocyte state transitions remain incompletely defined. Here, we identify the immunoproteasome subunit low molecular weight protein 2 (LMP2) as an important modulator of astrocyte functional remodeling following cerebral ischemia/reperfusion (I/R). Using global and astrocyte-specific knockout models, we demonstrate that LMP2 deficiency markedly reduces infarct volume, attenuates neuroinflammation, and improves neurological and cognitive outcomes. Mechanistically, LMP2 coordinately modulates inflammatory and reparative signaling networks by promoting nuclear factor kappa-B (NF-κB)-dependent inflammatory activation while constraining transforming growth factor-β1(TGF-β1)/SMAD family member 3 (Smad3)-associated reparative responses, thereby biasing astrocyte reactive states toward more inflammatory and maladaptive programs along the inflammatory-reparative continuum. Conversely, LMP2 inhibition promoted more adaptive and neuroprotective astrocyte-associated programs, enhanced neurotrophic support, and limited apoptosis under ischemic stress. Integrative transcriptomic and single-cell analyses further revealed that astrocyte responses exist along a continuum of functional states, with LMP2 influencing the distribution of astrocyte states rather than acting as a binary switch. Collectively, these findings uncover a previously unrecognized immunoproteasome-astrocyte regulatory axis involved in neuroinflammatory remodeling and highlight LMP2 as a promising target for precision modulation of post-ischemic brain injury.