UCP2 attenuates neural apoptosis and inflammation in spinal cord injury by inducing the acetylation of ANXA1 and activating the PI3K/AKT pathway.

Spinal cord injury (SCI) represents a prevalent form of mechanical trauma, frequently resulting in significant disability and mortality. Uncoupling protein 2 (UCP2) has been recognized for its neuroprotective properties; however, its specific role in SCI remains to be elucidated. This study aims to investigate the neuroprotective effects of UCP2 in the context of SCI and to further explore its downstream mechanisms of action. Through in vitro experiments, we demonstrated that UCP2 overexpression significantly improved cell viability and inhibited apoptosis and inflammatory responses in the lipopolysaccharides (LPS)-induced SCI cell model. Results of animal experiments showed that adeno-associated virus-mediated overexpression of UCP2 contributed to the recovery of SCI-afflicted rats, evidenced by improved Basso, Beattie, and Bresnahan scores, decreased water content in spinal tissues, reduced number of apoptotic cells in spinal cord. Mechanistic investigations revealed that UCP2 directly interacts with annexin A1 (ANXA1), enhancing its protein stability through acetylation at the K58 site. Furthermore, UCP2 was found to activate the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway by upregulating ANXA1 expression. Rescue assays indicated that knockdown of ANXA1 or inactivation of the PI3K/AKT pathway by LY294002 treatment partially neutralized the protective effects of UCP2 overexpression against apoptosis and inflammatory responses in LPS-stimulated BV-2 cells. Taken together, this study concludes that UCP2 ameliorates apoptosis and inflammatory responses in the SCI model by modulating acetylation-mediated protein stabilization of ANXA1 and activating the PI3K/AKT pathway.