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However, the underlying biological mechanisms and the precise relationship between depression and renal failure remain unclear. While interventions such as cognitive behavioral therapy and exercise have been shown to alleviate symptoms, the interplay between these conditions and their molecular pathways is poorly understood. An integrated analysis was conducted combining bioinformatics approaches and data from the UK Biobank (UKB) cohort. The UKB study revealed a significant association between renal failure and depression. Gene expression data from the Gene Expression Omnibus (GEO) database were analyzed to identify key co-expression modules using Weighted Gene Co-expression Network Analysis (WGCNA). Protein-protein interaction (PPI) networks were constructed using the STRING database, and immune cell infiltration was assessed with the CIBERSORT tool. UKB data confirmed a robust association between renal failure and depression. Bioinformatics analyses highlighted significant enrichment in pathways related to the acute inflammatory response, specific granule lumen, and immune receptor activity. PPI network analysis identified 23 hub genes, including <jats:italic>CYP4F2<\/jats:italic>, <jats:italic>KCNA3<\/jats:italic>, <jats:italic>KISS1R<\/jats:italic>,<jats:italic> LILRA5<\/jats:italic>, and <jats:italic>ZC3H12D<\/jats:italic>, as key players in the shared pathophysiology of ESRD and depression. Validation studies further emphasized the roles of <jats:italic>LILRA5<\/jats:italic>, <jats:italic>CYP4F2<\/jats:italic>, and <jats:italic>KISS1R<\/jats:italic> in these mechanisms. This study reveals novel insights into the molecular and immune interactions underlying the comorbidity of renal failure and depression. By combining cohort and bioinformatics analyses, we identify potential therapeutic targets and pathways that may inform innovative treatment strategies.<\/jats:p>","DOI":"10.1038\/s41598-025-04707-9","type":"journal-article","created":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T16:42:04Z","timestamp":1751388124000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Integrated analysis identifies key genes underlying the bidirectional association between depression and renal failure"],"prefix":"10.1038","volume":"15","author":[{"given":"Zhengqi","family":"Qiu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Nie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xu","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Du","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juntao","family":"Kan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emma Yun Zhi","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,7,1]]},"reference":[{"issue":"2","key":"4707_CR1","doi-asserted-by":"publisher","first-page":"5356","DOI":"10.4088\/JCP.14m09298","volume":"76","author":"PE Greenberg","year":"2015","unstructured":"Greenberg, P. 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