Work

Rab1a attenuates TNF-α-induced apoptosis and extracellular matrix degradation in nucleus pulposus cells by inhibiting PI3K-Akt signaling pathway overactivation

Year: 2026

Type: article

Abstract: OBJECTIVES: Intervertebral disc degeneration (IVDD) is a leading cause of low back pain, yet effective molecular targets remain limited. This study aims to investigate the role of Rab1a in IVDD and its underlying regulatory mechanism. METHODS: Rab1a expression was assessed in a rat tail puncture model and TNF-α-induced nucleus pulposus cells (NPCs). The therapeutic effect of Rab1a overexpression was evaluated via local lentiviral injection in vivo, and its impact on NPC apoptosis and extracellular matrix (ECM) metabolism was examined in vitro. For overexpression experiments, apoptosis was detected by immunofluorescence staining and TUNEL assay. For knockdown experiments, apoptosis was evaluated by flow cytometry. Transcriptome sequencing, KEGG pathway enrichment analysis, Western blot, and functional rescue experiments using SC79 and LY294002 were performed to explore the downstream mechanism. Additionally, Rab1a knockdown was performed using siRNA for reverse validation. RESULTS: Rab1a expression was downregulated in degenerated tissues and TNF-α-induced NPCs. Overexpression of Rab1a attenuated tissue degeneration in a rat IVDD model. Immunofluorescence and TUNEL staining revealed that Rab1a overexpression reduced NPC apoptosis and attenuated ECM degradation. Conversely, Rab1a knockdown under TNF-α stimulation exacerbated NPC apoptosis and ECM degradation, an effect that was quantitatively confirmed by flow cytometry and reversed by the PI3K inhibitor LY294002. Transcriptome sequencing and Western blot identified the PI3K-Akt pathway as a downstream target of Rab1a, and its overactivation was inhibited by Rab1a. The protective effects of Rab1a were reversed by the Akt activator SC79. CONCLUSION: Rab1a attenuates NPC apoptosis and ECM degradation by suppressing excessive activation of the PI3K-Akt signaling pathway, thereby delaying IVDD progression, positioning it as a potential therapeutic target for IVDD.

Source: International Immunopharmacology

DOI: 10.1016/j.intimp.2026.117013