JOURNAL/nrgr/04.03/01300535-202503000-00030/figure1/v/2026-05-05T095626Z/r/image-tiff Reducing the secondary inflammatory response, which is partly mediated by microglia, is a key focus in the treatment of spinal cord injury. Src homology 2-containing protein tyrosine phosphatase 2 (SHP2), encoded by PTPN11, is widely expressed in the human body and plays a role in inflammation through various mechanisms. Therefore, SHP2 is considered a potential target for the treatment of inflammation-related diseases. However, its role in secondary inflammation after spinal cord injury remains unclear. In this study, SHP2 was found to be abundantly expressed in microglia at the site of spinal cord injury. Inhibition of SHP2 expression using siRNA and SHP2 inhibitors attenuated the microglial inflammatory response in an in vitro lipopolysaccharide-induced model of inflammation. Notably, after treatment with SHP2 inhibitors, mice with spinal cord injury exhibited significantly improved hind limb locomotor function and reduced residual urine volume in the bladder. Subsequent in vitro experiments showed that, in microglia stimulated with lipopolysaccharide, inhibiting SHP2 expression promoted M2 polarization and inhibited M1 polarization. Finally, a co-culture experiment was conducted to assess the effect of microglia treated with SHP2 inhibitors on neuronal cells. The results demonstrated that inflammatory factors produced by microglia promoted neuronal apoptosis, while inhibiting SHP2 expression mitigated these effects. Collectively, our findings suggest that SHP2 enhances secondary inflammation and neuronal damage subsequent to spinal cord injury by modulating microglial phenotype. Therefore, inhibiting SHP2 alleviates the inflammatory response in mice with spinal cord injury and promotes functional recovery postinjury.

• lncRNA KRT8P41 potentially serves as an oncogenic lncRNA in chordoma. • miR-193a binds to lncRNA KRT8P41 and FUBP1 3′UTR. • LncRNA KRT8P41/miR-193a axis modulates chordoma cell aggressiveness through FUBP1.

Secondary inflammatory cascades after spinal cord injury (SCI) drive progressive neurological deterioration, with microglial activation as a key determinant of lesion progression. Kakkalide, a naturally occurring isoflavone, exhibits antioxidant and anti-inflammatory activities; however, its efficacy and mechanism of action in SCI remain insufficiently defined. To evaluate the therapeutic effects of kakkalide in SCI and delineate the molecular pathway through which it modulates microglia-driven neuroinflammation and functional recovery. SCI was induced in mice to assess the effects of kakkalide on locomotor function and secondary inflammation. In vitro, LPS-stimulated BV2 microglia were used to examine phenotypic polarization. Proteomic profiling and molecular docking were performed to identify candidate targets of kakkalide. Mechanistic dependence was tested using the SIRT3-selective inhibitor 3-TYP in both cell and animal models. Immunofluorescence, western blotting, qPCR, and assays of mitochondrial membrane potential and mitochondrial reactive oxygen species (mtROS) were used to interrogate microglial phenotypes, mitochondrial homeostasis, and related signaling pathways. Kakkalide treatment significantly reduced secondary inflammation and improved locomotor recovery in SCI mice. In BV2 microglia, kakkalide promoted a shift from a pro-inflammatory M1-like state toward an anti-inflammatory M2-like phenotype. Mechanistically, kakkalide restored mitochondrial homeostasis by activating BNIP3/NIX-dependent mitophagy, thereby suppressing mtROS accumulation. Proteomics and docking analyses identified sirtuin 3 (SIRT3) as a putative direct target of kakkalide. Consistently, kakkalide increased SIRT3 expression and activity in microglia, and SIRT3 activity was required for kakkalide-induced mitophagy. Notably, co-administration of 3-TYP abrogated the neuroprotective and functional benefits of kakkalide in vivo. Kakkalide mitigates SCI by directly engaging SIRT3 and activating BNIP3/NIX-mediated mitophagy, which stabilizes mitochondrial function, limits oxidative stress, and biases microglia toward an M2-like protective phenotype. These findings define a previously unrecognized mechanism for kakkalide in SCI and nominate the SIRT3-mitophagy axis as a tractable therapeutic target for neuroinflammatory disorders.