Work

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

Year: 2026

Type: article

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.

Source: Cell Death and Disease

DOI: 10.1038/s41419-026-09245-4

Authors: Chaorong Yu, Yanyan Wang, Haibin Xu, Yuang Zhang, Kanbin Wang, Jinyang Chen, Hanxu Huang, Han Zhou, Wenxuan Zhao, Xiaowen Jiang, Han Chen, Hongru Pan, He Xu, Qixin Chen, Erman Chen, Quan Zhou, Yujie Zhang

Institutions: Second Affiliated Hospital of Zhejiang University, Zhejiang University, First Affiliated Hospital Zhejiang University

Language: English

Topic: Spine and Intervertebral Disc Pathology

Subfield: Orthopedics and Sports Medicine

Field: Medicine

Domain: Health Sciences

Open Access status: gold

Estimated APC paid: $4,990

OpenAlex ID: W7225771048

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