In this study, we explored the neuroprotective properties of a novel Tat-CRYM recombinant protein, designed with a Tat domain to enhance blood-brain barrier permeability, within a transient cerebral ischemia using Mongolian gerbils. Our focus was on Ketimine reductase mu-crystallin (CRYM), a protein with widespread distribution in the brain, including areas like the cerebral cortex, corticospinal tract, and basal ganglia, and its diminished expression in neurodegenerative diseases such as Huntington's and Alzheimer's.We assessed the intracellular uptake of Tat-CRYM protein by NSC34 cells, revealing a concentration-dependent penetration efficiency. Following this, we administered the Tat-CRYM protein to a gerbil model of transient cerebral ischemia, observing a noticeable decrease in motor hyperactivity just one day post-surgery compared to a control group that underwent ischemia without any treatment.Four days after surgery, treatment with Tat-CRYM protein significantly mitigated neuronal cell death induced by ischemia. Moreover, we noted a reduction in reactive gliosis in the CA1 region that sustained damage.The results of our study underscore the potential therapeutic role of CRYM protein expression modulation in neuroprotection and the treatment of neurodegenerative diseases.