SCAP downregulation promotes intervertebral disc degeneration through 20-HETE mediated enhancement of macrophage pro-inflammatory responses

Abstract Intervertebral disc degeneration (IVDD) is increasingly recognized as an inflammation-driven disorder in which macrophage infiltration plays a pivotal role. Although metabolic pathways regulate macrophage immune responses, the immunometabolic mechanisms connecting macrophage activation and disc degeneration remain unclear. The sterol regulatory element–binding protein cleavage–activating protein (SCAP) was demonstrated as a key regulator of macrophage inflammatory responses. Using human annulus fibrosus (AF) tissues, a murine AF injury model, and macrophage-specific SCAP-knockout mice, we discovered that SCAP deficiency intensified macrophage pro-inflammatory activation and aggravated IVDD. Metabolomic profiling demonstrated a marked accumulation of 20-hydroxyeicosatetraenoic acid (20-HETE) in SCAP-deficient macrophages. Increased 20-HETE promoted inflammatory cytokine production and lipid peroxidation, whereas pharmacological inhibition of 20-HETE synthesis by HET0016 suppressed these effects and mitigated disc degeneration in vivo. Mechanistically, 20-HETE activated the cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS-STING) pathway and upregulated nuclear receptor coactivator 4 (NCOA4), thereby promoting lipid peroxidation. Silencing NCOA4 or blocking cGAS–STING signaling significantly decreased lipid peroxidation and pro-inflammatory responses. Our work uncovers SCAP downregulation as the initiating event of a 20-HETE-driven immunometabolic axis that links macrophage sterol sensing to redox dysregulation and disc degeneration, thereby revealing a novel metabolic–immune therapeutic target for IVDD.