The Role of TFEB-Regulated Autophagy in Intervertebral Disc Degeneration and Its Therapeutic Potential

Mengen Xue,1,* Zhengfa Jiang,2,* Zihao Wang,3,* Zongmian Song,4 Quan Zhou,1 Hao Han,4 Zhanhao Ma,1 Zhipeng Li,5 Liyuan Hu,3 Songfeng Chen,4 Chen Cao1 1Department of Surgery of Spine and Spinal Cord, Henan Provincial People’s Hospital; Zhengzhou University People’s Hospital, Zhengzhou, Henan, 450003, People’s Republic of China; 2Department of Orthopedics, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, Guangdong, People’s Republic of China; 3Department of Surgery of Spine and Spinal Cord, Henan Provincial People’s Hospital; Henan University People’s Hospital, Zhengzhou, 450003, Henan, People’s Republic of China; 4Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People’s Republic of China; 5The Second Department of Orthopedics, The Fifth Affiliated Hospital of Zhengzhou University, Henan, 450052, Zhengzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Songfeng Chen, Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People’s Republic of China, Tel +86 15936262527, Email [email protected] Chen Cao, Department of Surgery of Spine and Spinal Cord, Henan Provincial People’s Hospital; Zhengzhou University People’s Hospital, Zhengzhou, Henan, 450003, People’s Republic of China, Tel +86 13643820938, Email [email protected]: Intervertebral disc degeneration (IVDD) is a major cause of chronic low back pain, driven by nucleus pulposus cell (NPC) senescence, extracellular matrix imbalance, and chronic inflammation. Transcription Factor EB (TFEB), a master regulator of autophagy and lysosomal biogenesis, has emerged as a pivotal player in degenerative diseases. By modulating autophagy-related genes, TFEB promotes the clearance of damaged components and maintains metabolic homeostasis in NPCs. Its dysfunction impairs autophagic flux, exacerbating cellular apoptosis, oxidative stress, and ECM degradation, thereby accelerating IVDD progression. Critically, this review is the first to systematically synthesize evidence positioning TFEB at the nexus of these pathological processes, establishing it as an integrative therapeutic target. We detail the molecular regulation of TFEB and its dysfunction in IVDD. Furthermore, we evaluate emerging TFEB-targeted strategies and discuss the key translational challenges. This work provides not only a mechanistic synthesis but also a forward-looking perspective on overcoming bottlenecks in TFEB-based therapy for IVDD.Keywords: TFEB, intervertebral disc degeneration, autophagy flux, nucleus pulposus cells