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To further elucidate PDK1\u2019s pathogenic mechanisms, we conducted transcriptomic profiling. Samples were stratified into PDK1 high- and low-expression groups. GO and KEGG analyses demonstrated that upregulated DEGs were enriched in pathways involving \u03b2-CATENIN, cell adhesion and Ribosome, suggesting a potential role for WNT\/\u03b2-catenin signaling activation in ALS pathogenesis. To further validate the consistent risk association of PDK1 with ALS across multiple datasets, we utilized 4-month-old SOD1G93A transgenic mice, 4-month-old C9orf72 transgenic mice, and SOD1-overexpressing HEK293T cells. Significant upregulation of PDK1 mRNA was observed in all models, and a significant increase in protein abundance was found in SOD1G93A. This provides strong experimental evidence for the results of the MR study. These results indicate that PDK1 may affect the pathogenesis of amyotrophic lateral sclerosis through genetic variations and transcriptional dysregulation, and may play an important role in the occurrence and development of the disease.<\/jats:p>","DOI":"10.1186\/s13041-025-01248-0","type":"journal-article","created":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T10:21:30Z","timestamp":1759314090000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Integrated molecular data analysis confirms PDK1 as a candidate risk factor in ALS pathophysiology"],"prefix":"10.1186","volume":"18","author":[{"given":"Yuqian","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruiyun","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ni","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jialu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danyang","family":"Jing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruoyan","family":"Cui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Runchao","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2843-0769","authenticated-orcid":false,"given":"Jun","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,1]]},"reference":[{"key":"1248_CR1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2020227118","author":"D Buechel","year":"2021","unstructured":"Buechel D, Sugiyama N, et al. 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Other analyses were based on publicly available aggregated statistical data, which did not require ethical approval or consent.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"This manuscript does not include details, images or videos relating to an individual person; therefore, consent for publication is not required, beyond the informed consent provided by all study participants as described above.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"Not applicable.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Clinical trial number"}},{"value":"The authors declare no competing interests.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"76"}}