Macrophage Lipid Homeostasis Drives IVDD via a Senescence‐Dependent Impairment of Efferocytosis

Abstract

ABSTRACT Intervertebral disc degeneration (IVDD) is a major contributor to low back pain, but the immune‐metabolic events that sustain disc inflammation remain poorly defined. Here, we investigated whether disturbed macrophage lipid handling promotes IVDD by coupling cellular senescence to defective efferocytosis. Clinical magnetic resonance imaging and biochemical profiling showed that advanced IVDD was accompanied by increased disc fat fraction and systemic lipid abnormalities. Mendelian randomisation, bulk transcriptomics, machine‐learning modelling and single‐cell RNA sequencing further linked lipid metabolic disturbance to immune remodelling in degenerative discs, and identified TIAM2, SLC44A4, PPT1 and PTGDS as lipid metabolism‐related hub genes associated with IVDD. At the single‐cell level, disc macrophages with low glycerophospholipid metabolism scores showed higher senescence activity, a more inflammatory polarisation state and reduced efferocytosis‐related signatures. Functional studies in bone marrow‐derived macrophages indicated that lipid overload promoted lipid droplet accumulation, lipid peroxidation, impaired lipophagy and cholesterol efflux, activation of the p53/p21 senescence pathway, and reduced apoptotic nucleus pulposus cell clearance. Restoring lipid homeostasis with rosuvastatin enhanced lipophagy, recovered ABCA1/ABCG1‐mediated cholesterol export, attenuated macrophage senescence and inflammatory activation and improved efferocytosis. In a rat needle puncture model, local rosuvastatin delivery alleviated disc structural damage, preserved proteoglycan content, balanced extracellular matrix metabolism and reduced macrophage senescence and inflammatory markers. In conclusion, this study supports macrophage lipid homeostasis as an important regulator of IVDD‐associated immune dysfunction through senescence‐associated impairment of efferocytosis.