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The underlying pathomechanisms remain incompletely understood, and specific disease markers are sparse. This study aimed to characterize the myocardial transcriptome and proteome in ACM patients and assess whether key identified molecules were also detectable in plasma and tissue samples.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>Myocardial tissues were obtained from ACM and dilated cardiomyopathy (DCM) patients as well as healthy controls (n = 10\/group). Transcriptomic profiling was performed by RNA sequencing and proteomic profiling by label-free liquid chromatography\u2013tandem mass spectrometry. Differential expression and pathway enrichment analyses were performed to identify key biological processes. Selected targets were validated by tissue immunofluorescence and plasma ELISA. Transcriptomic analysis revealed 3030 dysregulated mRNAs in ACM versus healthy controls and 120 versus DCM. Enriched clusters in ACM versus healthy controls were related to immune activation, inflammation, extracellular matrix remodelling and mitochondrial stress; redox and metabolic processes, cell junction regulation and immune responses were enriched clusters in ACM versus DCM. Proteomics identified 206 and 65 differentially expressed proteins, respectively. Three novel proteins, UCHL1, OCIAD1 and desmoyokin, were consistently up-regulated at transcript and protein levels. The latter two were confirmed in myocardial tissue staining and showed elevated plasma levels in ACM compared with DCM and controls.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This integrated transcriptomic and proteomic study of myocardial tissue and plasma from patients with ACM compared with those with DCM and healthy controls, identified key dysregulated pathways, involving immune response, inflammation and oxidative and mitochondrial stress. Desmoyokin and OCIAD1, in particular, may represent specific candidate biomarkers for ACM.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ehf2.70013","type":"journal-article","created":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T06:16:24Z","timestamp":1763014584000},"page":"4419-4430","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Transcriptomic and Proteomic Profiling Shows Dysregulated Immune and Metabolic Pathways in Arrhythmogenic Cardiomyopathy"],"prefix":"10.1093","volume":"12","author":[{"given":"Deniz","family":"Akdis","sequence":"first","affiliation":[{"name":"Department of Cardiology, University Hospital Zurich and University of Zurich , Zurich ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lukas","family":"Weidmann","sequence":"additional","affiliation":[{"name":"Department of Nephrology, University Hospital Zurich and University of Zurich 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