Antidiabetic DPP4 inhibitor Attenuates Intervertebral Disc Degeneration via Macrophage‐Nucleus Pulposus Cell Crosstalk

Background and purpose Intervertebral disc degeneration (IVDD), a leading cause of low back pain, lacks effective disease‐modifying therapies. Diabetes exacerbates IVDD risk, but the causal mechanisms and therapeutic potential of glucose‐lowering agents remain underexplored. This study aimed to identify glucose‐lowering drug targets strongly associated with IVDD using Mendelian randomisation (MR) and to validate the therapeutic efficacy and mechanisms of sitagliptin, an inhibitor of dipeptidyl peptidase 4 (DPP4), in alleviating IVDD progression. Experimental approach Two‐sample MR analysis was performed to assess causal links between glucose‐lowering drug targets and IVDD risk using genome‐wide association studies data. A tail puncture model in male SD rats, interactive culture systems of nucleus pulposus (NP) cells and macrophages were established to evaluate effects of sitagliptin. Molecular techniques and network pharmacology were employed to elucidate mechanisms. Key results MR analysis identified DPP4 as a causal risk factor for IVDD. DPP4 expression was elevated in degenerated human and rat NP tissues. Sitagliptin alleviated disc height loss, preserved extracellular matrix (ECM) integrity, and reduced histological degeneration in vivo. Sitagliptin suppressed macrophage infiltration and interfered with polarisation. It disrupted the NF‐κB/NLRP3/IL‐1β axis in NP cells, attenuating inflammasome activation, pro‐inflammatory cytokine release and ECM degradation. Conclusion and implications DPP4 was a causal driver of IVDD, and its inhibition by sitagliptin mitigated degeneration by disrupting the pathogenic positive feedback loop between macrophages and NP cells. These findings reposition sitagliptin, a clinically approved antidiabetic drug, as a promising therapeutic candidate for IVDD, highlighting the translational potential of targeting DPP4 and its downstream inflammatory cascades.