Targeting AMPK signaling in nucleus pulposus cells ameliorates spaceflight microgravity-induced intervertebral disc degeneration

Long-duration spaceflight elicits spinal impairments, including bone loss and intervertebral disc degeneration (IVDD). As the connective hub of the entire spine, the intervertebral disc (IVD) plays a pivotal role in maintaining spinal stability. However, the molecular mechanisms through which space microgravity mediates IVDD remain elusive, and the core spinal component responsible for mechanical load-bearing and the maintenance of spinal mechanical homeostasis has not been identified. Herein, we identified for the first time that space microgravity induces nucleus pulposus (NP) degeneration via PIEZO1. Analysis of samples from patients with IVDD indicates downregulated PIEZO1 expression in NP cells. Specific Piezo1 deficiency in NP cells not only disrupts the extracellular matrix (ECM) metabolism of NP but also impairs the homeostasis of the annulus fibrosus and cartilage endplate. Mechanistically, Piezo1 deficiency drives NP cell apoptosis and alters their secretory profile by activating the AMP-activated protein kinase (AMPK) signaling pathway, thereby mediating functional spinal unit (FSU) dysfunction through paracrine regulation. Targeted delivery of AMPK inhibitors to NP tissue markedly mitigates the progression of IVDD induced by mechanical instability. Together, our findings uncover the central role of the NP in mechanical response and its paracrine function within the FSU for the first time, providing a potential therapeutic strategy for IVDD treatment and astronaut spinal protection.