OSBPL10 alleviates neuronal ferroptosis via lysosomal membrane repair in a PS-dependent manner after spinal cord injury.

Spinal cord injury (SCI) exerts severe adverse effects on patients, leading to impaired motor functions in segments remote from the injury site. Following SCI, lysosomes are damaged due to inflammatory microenvironment, and the repair of such damage requires a substantial supply of lipids. Studies have demonstrated that lipid transfer proteins (LTPs) play a pivotal role in the repair process of neuronal organelles. However, whether these proteins regulate functional recovery after SCI and their underlying mechanisms remain elusive. Through RNA sequencing and human cerebrospinal fluid enzyme-linked immunosorbent assay (ELISA) analyses, we verified that OSBPL10 is significantly downregulated in the acute phase of SCI and may serve as a protective factor against SCI. The Basso Mouse Scale (BMS), Nissl staining, and two-dimensional (2D) gait analysis were employed to evaluate functional recovery. Western blotting and immunofluorescence assays were performed to detect the expression changes of proteins associated with autophagy, ferroptosis, oxidative stress, and lysosomal membrane permeabilization (LMP) related proteins. Finally, molecular docking and rescue experiments using lipid synthesis inhibitors further confirmed that OSBPL10 ameliorate LMP by transferring PS to lysosomes, thereby promoting autophagic flux. Collectively, our findings conclude that OSBPL10 overexpression alleviates autophagic flux impairment, ferroptosis, and oxidative stress after SCI through PS-mediated lysosomal repair, thus facilitating post-injury neurological function recovery and holding promising potential for clinical application.