Macrophage reprogramming as a therapeutic avenue in intervertebral disc degeneration: Insights into pharmacological targeting.

Intervertebral disc degeneration (IDD), a major contributor to chronic low back pain, involves inflammation, extracellular matrix (ECM) degradation, and nucleus pulposus cell apoptosis. Recent studies have highlighted the critical role of macrophage polarization, which influences inflammation, tissue repair, and disc homeostasis. Macrophages can polarize into pro-inflammatory M1 and anti-inflammatory M2 phenotypes. M1 macrophages exacerbate IDD by releasing cytokines such as IL-1β and TNF-α, while M2 macrophages promote tissue repair and ECM synthesis. The disc microenvironment-marked by hypoxia, acidity, and inflammatory mediators-critically shapes macrophage behavior. Key signaling pathways, including NF-κB, STAT, PI3K-Akt, and Keap1-Nrf2, regulate this polarization and affect IDD progression. Emerging therapeutic strategies aim to reprogram macrophage polarization, using stem cell-derived exosomes, miRNA/lncRNA-based gene therapy, anti-inflammatory drugs, and biomaterial-based delivery systems, to shift M1 to M2 phenotypes. This review summarizes current knowledge on macrophage polarization in IDD, the regulatory effects of the disc microenvironment, and associated molecular pathways. Furthermore, we discuss innovative immunomodulatory strategies targeting macrophage reprogramming. Future research should integrate multi-omics approaches, advanced biomaterials, and precise immune regulation to develop effective interventions for IDD.