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Lysophosphatidylcholine Acyltransferase 1-Phosphatidylcholine Axis Protects Nucleus Pulposus Cells From Ferroptosis by Facilitating Lysosomal Repair via Interaction With the Endoplasmic Reticulum
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DOI：10.14245/ns.2550918.459.png)
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Abstract
En 中文
Objective: Intervertebral disc degeneration (IDD), a prevalent musculoskeletal disorder, imposes significant socioeconomic and health care burdens worldwide. Despite its clinical impact, the molecular mechanisms driving IDD pathogenesis remain poorly characterized, and effective pharmacological interventions are urgently needed. This study elucidated the molecular mechanisms underlying IDD progression through multiomics integration. Methods: We performed systematic transcriptomic, proteomic, metabolomic, and lipidomic profiling of human degenerated nucleus pulposus (NP) tissues to identify disease-associated molecular signatures and therapeutic targets. Functional validation experiments were conducted using in vitro and ex vivo models of IDD. Results: Multiomics analyses revealed that lysosomal membrane lipid remodeling plays a critical role in IDD progression. Dysregulation of lysosomal phosphatidylcholine (PC) metabolism caused by reduced lysophosphatidylcholine acyltransferase 1 (LPCAT1) expression led to lysosomal membrane permeabilization (LMP) and subsequent ferroptosis in NP cells. Mechanistically, the LPCAT1-PC axis was identified as a key regulatory pathway: LPCAT1 downregulation in IDD correlated with decreased lysosomal PC content, impaired membrane stability and increased LMP-driven ferroptosis. Conversely, LPCAT1 overexpression increased the number of endoplasmic reticulum-lysosome contact sites, facilitating phospholipid transfer and lysosomal membrane repair. This restoration of lysosomal integrity effectively suppressed ferroptotic cell death. Conclusion: Our findings establish the LPCAT1-PC axis as a potential protective mechanism against IDD by maintaining lysosomal homeostasis through interorganellar lipid trafficking. This study provides the first evidence linking lysosomal lipid composition, membrane stability, and ferroptosis in NP cells, offering new therapeutic strategies targeting lipid metabolism and organelle crosstalk for IDD management.
Keywords:
Intervertebral disc degeneration
Ferroptosis
Lysosomal membrane permeabilization
Lysophosphatidylcholine acyltransferase 1
Phosphatidylcholine
Endoplasmic reticulum
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