Immunometabolism: A Novel Therapeutic Target and Its Pharmacological Modulation for Intervertebral Disc Degeneration.

Intervertebral disc degeneration (IDD) is a leading cause of low back pain (LBP) and imposes a substantial social and economic burden. Current treatments mainly relieve symptoms but rarely halt or reverse disc degeneration, and key gaps remain in our understanding of its pathophysiology. Accordingly, promoting intervertebral disc regeneration (IVDR) has been proposed as a potential therapeutic aim. Immunometabolism, which refers to the bidirectional interplay between immune responses and cellular metabolism, is increasingly recognized as a key factor affecting the balance of disc homeostasis and degeneration and has become an emerging research focus. In this review, we synthesize evidence supporting a dual and context-specific role of immunometabolism in IDD and IVDR. On the one hand, certain immune cells and anabolic cytokines or growth factors may promote a regenerative microenvironment by supporting disc cell survival and extracellular matrix (ECM) synthesis. On the other hand, pro-inflammatory mediators and metabolic disorders, including oxidative stress, mitochondrial dysfunction, and lipid or amino acid imbalance, drive a catabolic cascade that accelerates ECM breakdown and cellular senescence. We summarize current knowledge regarding key immune cell subsets, cytokine networks, and metabolic pathways implicated in IDD pathogenesis and IVDR, and we discuss how these immunometabolic principles are being leveraged in emerging interventions such as stem cell-based therapies, gene therapy, and advanced biomaterials. By integrating mechanistic insights with translational advances, this review aims to clarify actionable immunometabolic targets and to inform the rational development of regenerative strategies for disc-related diseases.