Mn-MIL-100@AKG alleviates intervertebral disc degeneration by regulating mitophagy

Currently, the therapy of intervertebral disc degeneration (IDD) mostly focuses on basic molecular causes. Research on the alterations of metabolites in the intervertebral disc prior to and following intervertebral disc degeneration (IDD) remains inadequate, with even less therapeutic options available for metabolites. In contrast to traditional investigations of molecular mechanisms, it has been shown that a reciprocal relationship exists between the nutritional metabolism of the intervertebral disc and the molecular mechanisms of degeneration. Impaired energy metabolism in deteriorated nucleus pulposus cells exacerbates numerous degenerative phenotypes within the cells. This work investigated the metabolic alterations in the intervertebral disc after the creation of inflammatory degeneration models and illustrated the therapeutic benefits of α-ketoglutarate (AKG) on degenerated nucleus pulposus cells. This study introduces the first demonstration of a metal-organic framework (MOF)-based delivery system (Mn-MIL-100@AKG) for α-ketoglutarate (AKG) aimed at treating intervertebral disc degeneration (IDD), revealing a unique mode of mitophagy control through the HIF-1α-BNIP3-LC3B axis. Our study elucidated the critical function of autophagy regulation via the HIF-1α-BNIP3-LC3B axis in mitigating NPC degeneration and established a MOF-based AKG drug delivery system, offering a novel approach for the treatment of IDD.