Chondroitin Sulfate Reinforces Mitochondrial Redox Homeostasis to Enable Integrated Intervertebral Disc Regeneration

Intervertebral disc degeneration (IVDD), characterized by oxidative stress, mitochondrial dysfunction, and extracellular matrix (ECM) breakdown, is a major contributor to low back pain. Current regenerative strategies often fail to address both the biological and structural aspects of IVDD in an integrated manner. Here, we demonstrate that chondroitin sulfate (CS) exerts a dual therapeutic role by enhancing endogenous antioxidant defenses and promoting anabolic ECM synthesis in both annulus fibrosus cells (AFCs) and nucleus pulposus cells (NPCs). Mechanistically, CS activates the integrin α4β1-PI3K-Akt signaling pathway, preserving mitochondrial integrity and restoring redox homeostasis. Furthermore, we developed an injectable, multifunctional PVA/collagen/CS hydrogel that integrates mechanical support, bioactivity, and targeted CS delivery to enable unified repair of the disc’s biphasic structure. In a rat IVDD model, this hydrogel effectively preserved disc architecture, restored disc height and MRI signal, and upregulated key matrix and antioxidant markers, demonstrating coordinated repair of both the annulus fibrosus (AF) and the nucleus pulposus (NP). Our study establishes CS as a potent dual-function agent and presents an integrated hydrogel-based strategy for functional disc regeneration.