{"doi":"10.1093/eurheartj/ehaf024","title":"Atrial cardiomyocyte-restricted cleavage of gasdermin D promotes atrial arrhythmogenesis","abstract":"BACKGROUND AND AIMS: Enhanced inflammatory signalling causally contributes to atrial fibrillation (AF) development. Gasdermin D (GSDMD) is an important downstream effector of several inflammasome pathways. However, the role of GSDMD, particularly the cleaved N-terminal (NT)-GSDMD, in non-immune cells remains elusive. This study aimed to elucidate the function of NT-GSDMD in atrial cardiomyocytes (ACMs) and determine its contribution to atrial arrhythmogenesis. METHODS: Human atrial appendages were used to assess the protein levels and localization. A modified adeno-associated virus 9 was employed to establish ACM-restricted overexpression of NT-GSDMD in mice. RESULTS: The cleavage of GSDMD was enhanced in ACMs of AF patients. Atrial cardiomyocyte-restricted overexpression of NT-GSDMD in mice increased susceptibility to pacing-induced AF. The NT-GSDMD pore formation facilitated interleukin-1β secretion from ACMs, promoting macrophage infiltration, while up-regulating 'endosomal sorting complexes required for transport'-mediated membrane-repair mechanisms, which prevented inflammatory cell death (pyroptosis) in ACMs. Up-regulated NT-GSDMD directly targeted mitochondria, increasing mitochondrial reactive oxygen species (ROS) generation, which triggered proarrhythmic calcium-release events. The NT-GSDMD-induced arrhythmogenesis was mitigated by the mitochondrial-specific antioxidant MitoTEMPO. A mutant NT-GSDMD lacking pore-formation capability failed to cause mitochondrial dysfunction or induce atrial arrhythmia. Genetic ablation of Gsdmd prevented spontaneous AF development in a mouse model. CONCLUSIONS: These findings establish a unique pyroptosis-independent role of NT-GSDMD in ACMs and arrhythmogenesis, which involves ROS-driven mitochondrial dysfunction. Mitochondrial-targeted therapy, either by reducing ROS production or inhibition of GSDMD, prevents AF inducibility, positioning GSDMD as a novel therapeutic target for AF prevention.","journal":"European Heart Journal","year":2025,"id":510278,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":21,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.961,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1367312,"name":"Pascal Martsch","orcid":null,"position":1,"is_corresponding":false},{"id":628619,"name":"Xiaohui Chen","orcid":"0000-0003-3723-513X","position":2,"is_corresponding":false},{"id":1367313,"name":"Enrique Martinez","orcid":null,"position":3,"is_corresponding":false},{"id":574859,"name":"Luge Li","orcid":"0000-0002-4145-2607","position":4,"is_corresponding":false},{"id":831338,"name":"Jia Song","orcid":"0000-0002-0815-208X","position":5,"is_corresponding":false},{"id":1366458,"name":"Theresa Poppenborg","orcid":"0009-0000-9741-9112","position":6,"is_corresponding":false},{"id":832845,"name":"Florian Bruns","orcid":"0000-0001-6269-5061","position":7,"is_corresponding":false},{"id":1088565,"name":"Jong Hwan Kim","orcid":"0000-0001-6201-9602","position":8,"is_corresponding":false},{"id":288857,"name":"Markus Kamler","orcid":"0000-0001-6608-8496","position":9,"is_corresponding":false},{"id":295762,"name":"James F. Martin","orcid":"0000-0002-7842-9857","position":10,"is_corresponding":false},{"id":316353,"name":"Issam Abu-Taha","orcid":"0000-0002-2298-8959","position":11,"is_corresponding":false},{"id":58218,"name":"Dobromir Dobrev","orcid":"0000-0002-4612-117X","position":12,"is_corresponding":false},{"id":288858,"name":"Na Li","orcid":"0000-0003-1307-3375","position":13,"is_corresponding":false},{"id":1024343,"name":"Yue Yuan","orcid":"0009-0003-3723-8178","position":0,"is_corresponding":true}],"reference_count":58,"raw_metadata":null,"created_at":"2026-07-19T02:47:36.538276Z","pmid":"39927987","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}