Molecular mechanism by which the imbalance of the functional network of tissue inhibitors of metalloproteinases drives intervertebral disc degeneration

• TIMP subtypes exhibit distinct and context-dependent roles in intervertebral disc degeneration, with TIMP1 showing dual early-protective/late-depletion effects, TIMP2 and TIMP3 exerting protective functions, and TIMP4 involvement via miR-155-5p/FGF2 axis. • Epigenetic regulation, including m6A modification (WTAP/YTHDF2 axis) and microRNAs (miR-222, miR-185-5p), critically controls TIMP expression and contributes to the MMP/TIMP imbalance driving disc degeneration. • The MMP/TIMP balance is a central node integrating inflammatory, oxidative stress, and mechanical signals, with NF-κB, AP-1, and ERK/p38 pathways forming a pathological amplification network. • Emerging multi-modal therapies, such as photobiomodulation, stem cell exosomes, and irisin, show promise in restoring matrix homeostasis by targeting TIMP/MMP balance, offering potential for precision treatment of intervertebral disc degeneration.