{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T05:05:32Z","timestamp":1790139932307,"version":"4.0.1"},"reference-count":44,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"content-version":"vor","delay-in-days":2,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Gene Medicine"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Intervertebral disc degeneration (IVDD) is closely associated with cellular senescence and defective autophagic degradation, but the molecular heterogeneity and functional significance of lysosome\u2010related alterations remain incompletely understood. We integrated bulk transcriptomic datasets (GSE56081 and GSE70362) and single\u2010cell RNA\u2010sequencing data (GSE153066) using consensus clustering, weighted gene coexpression network analysis, machine\u2010learning algorithms, immune\u2010signature analysis, and covariate\u2010adjusted correlation testing. Candidate genes were evaluated in human and rat disc tissues, and PLD3 was further examined by knockdown and overexpression in H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    \u2010treated nucleus pulposus cells (NPCs). Lysosomal function was assessed using LysoTracker staining, cathepsin activity, and autophagy\u2010related markers, and the preclinical effects of lithocholic acid (LA) were evaluated in cultured NPCs and a rat needle\u2010puncture model. Two lysosome\u2010related molecular subtypes were identified: a senescence\/inflammation\u2010enriched subtype and a metabolism\u2010enriched subtype. The lysosomal gene\u2010signature score was positively associated with the senescence score after adjustment for total cellular transcript counts (partial\n                    <jats:italic>r<\/jats:italic>\n                    \u2009=\u20090.422; empirical permutation\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.0005), supporting coordinated transcriptional activation rather than enhanced degradative function. HYAL1, MMD, PLD3, and ANK3 were prioritized as candidate hub genes. PLD3 knockdown aggravated H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    \u2010induced lysosomal impairment, matrix degeneration, and senescence, whereas PLD3 overexpression produced opposing protective effects. LA partially improved acidic lysosomal compartments, cathepsin activity, autophagic degradation, and senescence\u2010associated changes in\u00a0vitro and attenuated degeneration\u2010associated histological and molecular alterations in\u00a0vivo. These findings reveal distinct lysosome\u2010related phenotypes in IVDD, functionally support PLD3 as a contributor to lysosomal homeostasis, and suggest that lysosome\u2010modulating interventions may have therapeutic potential.\n                  <\/jats:p>","DOI":"10.1002\/jgm.70109","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T10:36:16Z","timestamp":1788431776000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Lysosomal Dysfunction Is Associated With Intervertebral Disc Degeneration: Multiomics and Machine Learning Identify Molecular Subtypes and Hub Genes"],"prefix":"10.1002","volume":"28","author":[{"given":"Yang","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Orthopedic Surgery Changzheng Hospital, Navy Medical University  Shanghai 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