HDAC1 maintains metabolic homeostasis in nucleus pulposus cells via post-translational modification interactions with YBX1

Abstract

Intervertebral disc degeneration is characterized by the metabolic dysregulation of nucleus pulposus cells, which is regulated by complex post-translational modifications, manifesting as extracellular matrix remodeling and inflammatory microenvironment formation. We demonstrated the progressive downregulation of HDAC1 during disc degeneration. HDAC1 mediates the deacetylation and ubiquitination-dependent degradation of YBX1. The downregulation of HDAC1 results in YBX1 accumulation, compromising extracellular matrix synthesis in nucleus pulposus cells while enhancing the degradation processes. Furthermore, the accumulated YBX1 stimulates chemokine expression, facilitating the development of an inflammatory microenvironment. Targeting this critical axis, we developed SU056@GelMA to deliver the YBX1 inhibitor SU056, mitigating the metabolic disruption induced by YBX1 accumulation. Intervertebral disc degeneration (IVDD) is a leading cause of disability, with nucleus pulposus cells (NPCs) undergoing metabolic changes that lead to extracellular matrix (ECM) degradation and inflammation. This study explores the role of histone deacetylase 1 (HDAC1) in IVDD, revealing its downregulation in degenerative discs and its critical role in maintaining NPC metabolic homeostasis. Researchers used RNA sequencing and protein analysis to demonstrate that HDAC1 regulates ECM synthesis and degradation by deacetylating Y-box-binding protein 1 (YBX1), promoting its ubiquitination and degradation. HDAC1 deficiency led to YBX1 accumulation, promoting ECM degradation and inflammation. The study introduced SU056@GelMA, a hydrogel delivering the YBX1 inhibitor SU056, which improved ECM synthesis and reduced inflammation in rat and rabbit IVDD models. These findings highlight the potential of HDAC1 as a therapeutic target, suggesting future research on post-translational modifications in IVDD treatment. "This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author. "