Inhibition of PLA2G15 Alleviates Palmitic Acid-Induced Lysosomal Membrane Permeabilization in Human Nucleus Pulposus Cells During Intervertebral Disc Degeneration

<h4>Objective</h4>Intervertebral disc degeneration (IDD) imposes substantial economic and healthcare burdens, yet its mechanisms remain incompletely understood and effective pharmacological treatments are lacking. This study aimed to elucidate key factors driving IDD progression, specifically investigating lysosomal dysfunction and lysosomal membrane permeability (LMP) in human nucleus pulposus (NP) cells, and to identify potential therapeutic targets.<h4>Methods</h4>We employed an integrative multiomics approach (transcriptomics, proteomics, metabonomics, and lipomics) combined with functional validation. Luciferase reporter assays investigated transcriptional regulation. The role of PLA2G15 in palmitic acid (PA)-induced lysosomal dysfunction was assessed in vitro and in vivo.<h4>Results</h4>Integrated analysis identified lysosomal dysfunction and increased LMP as the key molecular features in human NP cells during IDD. PLA2G15 expression was significantly upregulated under PA overload conditions. PLA2G15-mediated PA-induced alterations in lysosomal membrane lipid composition and subsequent LMP by hydrolyzing lysosomal membrane phospholipids. The transcription factor C/EBPα directly bound the PLA2G15 promoter, regulating its transcription under PA overload conditions. Crucially, in vivo inhibition of PLA2G15 mitigated PA-induced LMP by restoring normal lysosomal membrane lipid composition, thereby attenuating IDD progression.<h4>Conclusions</h4>This study demonstrates that PLA2G15 inhibition mitigates PA-induced IDD progression by preventing lysosomal dysfunction and LMP. Our findings reveal the significance of lysosomal membrane lipid composition alterations in human NP cells and identify PLA2G15 as a potential therapeutic target for IDD treatment.