IFT88/Kindlin-2 Signaling Prevents Mechanical Overloading-Induced PANoptosis of Nucleus Pulposus Cells by Activating FOXP1 SUMOylation.

Intervertebral disc (IVD) degeneration (IDD) involves nucleus pulposus (NP) cell death, but its mechanisms are unclear. PANoptosis is a novel cell death pattern whose role in IDD remains elusive. This study investigates whether PANoptosis contributes to mechanical overloading-induced NP cell death and explores its underlying mechanisms. We evaluated PANoptosis in NP cells from human degenerated IVD tissues, aged mice, lumbar spine instability model, and an in vitro mechanical compression system. Results indicated that PANoptosis-related proteins were upregulated in NP cells from degenerated IVDs, as well as in those subjected to mechanical overloading both in vivo and in vitro. To confirm its functional role, we inhibited PANoptosis by interfering PANoptosis sensor Z-DNA-binding protein 1 (ZBP1). Results showed that ZBP1 inhibition partially reversed this upregulation, reduced NP cell death, and alleviated IDD. Mechanistically, we found Kindlin-2 loss promoted PANoptosis in NP cells by suppressing forkhead box P1 (FOXP1) SUMOylation and increasing ZBP1 promoter activity. Furthermore, mechanical overloading downregulated Kindlin-2 by impairing ciliary intraflagellar transport 88 (IFT88), thereby exacerbating PANoptosis and IDD. We show that ciliary IFT88 influences Kindlin-2, which protects NP cells from mechanical overloading-induced PANoptosis by enhancing FOXP1 SUMOylation. This pathway may offer a new therapeutic target for IDD.