SIRT1/PGC-1α Axis and CPT1A-Mediated Metabolic Reprogramming Reshape Macrophage Polarization to Ameliorate Intervertebral Disc Degeneration.

Abstract

Intervertebral disc degeneration (IDD) is a leading cause of chronic low back pain, and macrophages play a pivotal regulatory role through metabolic reprogramming that governs M1/M2 polarization. This study aimed to elucidate how the Sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) axis and carnitine palmitoyltransferase 1A (CPT1A)-mediated metabolic reprogramming regulate macrophage polarization in IDD using single-cell RNA sequencing (scRNA-seq), bulk RNA sequencing (bulk RNA-seq), and isotope tracing. A puncture-induced IDD rat model was established. Exploratory scRNA-seq and bulk RNA-seq revealed an increased M1 macrophage trend and identified SIRT1, PGC-1α, and CPT1A as candidate regulators of glycolysis and fatty acid oxidation (FAO). Immunofluorescence, Western blot, and flow cytometry confirmed M1/M2 polarization changes. Lentiviral-mediated overexpression, PGC-1α/CPT1A knockdown rescue, and [¹³C]-glucose and [¹³C]-palmitate isotope tracing demonstrated that activation of the SIRT1/PGC-1α axis and CPT1A enhanced oxidative phosphorylation (OXPHOS) and FAO, reduced glycolytic activity, promoted M2 polarization, suppressed inflammatory cytokines, and mitigated extracellular matrix (ECM) degradation. In vivo administration of the SIRT1 agonist SRT1720 or CPT1A agonist C75 alleviated IDD progression. This study indicates that the SIRT1/PGC-1α/CPT1A axis regulates macrophage polarization through metabolic reprogramming and provides potential therapeutic targets for IDD.