{"doi":"10.3389/fphys.2025.1581282","title":"Editorial: Cell death programs in the pathogenesis of heart disease","abstract":"Cell death plays an important role in the pathogenesis of multiple forms of heart disease such as myocardial infarction, myocarditis, cardiomyopathies, drug-induced cardiotoxicity, and heart failure of diverse etiologies. Apoptosis is the first identified form of regulated cell death, which is characterized by cell shrinkage, membrane blebbing, chromatin condensation, and DNA fragmentation, without loss of plasma membrane integrity or inflammatory response (Danial and Korsmeyer, 2004). In contrast, necrosis had long been regarded as an unregulated process characterized by loss of plasma membrane integrity, cell swelling and lysis, and marked tissue inflammation and fibrosis (Edinger and Thompson, 2004). However, recent studies have identified multiple regulated necrosis programs, including necroptosis, ferroptosis, pyroptosis, parthanatos, mitochondria-mediated necrosis, and other regulated necrotic processes (Del Re et al., 2019).The discovery of regulated necrosis opens a new avenue to target necrosis for the treatment of heart disease, which was deemed impossible in the past. These cell death programs are often activated by distinct extracellular or intracellular signals under different physiological or pathological settings. The goal of this review series is to provide an overview of recent findings pertaining to the role of various cell death programs in the pathogenesis of heart diseases (Grisanti, 2024;Bhatti, 2024;Rowland, 2024;Fatima, 2024).Apoptosis can be engaged through two primary pathways: the mitochondria-dependent intrinsic pathway or the extrinsic pathway which involves ligand-mediated activation of death receptors on the plasma membrane. While research on cardiac apoptotic death mechanisms have primarily focused on delineating the molecular effectors of intrinsic apoptosis as well as extrinsic apoptosis mediated by the pro-inflammatory cytokines like tumor necrosis factor (TNF)-α in the heart, Grisanti (2024) sheds light on the emerging roles of TRAIL (TNF-related apoptosis-inducing ligand), a member of the TNF superfamily known for its role in cancer cell apoptosis, but is less studied in the context of the heart. TRAIL and its receptors, particularly DR5 (death receptor 5), have been associated with key cardiovascular disease risk factors including smoking, diabetes, and hypertension, and as well as cardiac diseases including arrhythmias, atherosclerosis, acute myocardial infarction, and heart failure. Notably, the relationship between TRAIL and cardiovascular disease may be complex, as human studies suggest both pro-apoptotic and cardioprotective effects. This duality underscores the importance of defining TRAIL's roles in different cardiac cell types and pathologies, which could pave the way for future development of TRAIL-targeted therapies.Beyond apoptosis, this research topic also highlights two emerging forms of regulated necrosis that can also contribute to cardiac disease: ferroptosis (Fatima, 2024) and pyroptosis (Bhatti, 2024). Ferroptosis is a form of regulated cell death characterized by iron-dependent lipid peroxidation. Intracellular iron overload, which can be triggered by dysregulated autophagy of ferritin (ferritinophagy) or aberrant heme degradation, induces lipid peroxidation via the Fenton reaction and cytotoxic damage. Moreover, inactivation of key suppressors of lipid peroxidation, including glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein-1 (FSP-1), can also induce ferroptotic death. Pyroptosis on the other hand, is a form of regulated necrosis associated that is closely associated with inflammation. In this form of death, activation of inflammationassociated caspases through canonical (caspase-1 dependent) or non-canonical (caspase-4/-5/-11 dependent) pathways lead cleavage and activation of pore-forming gasdermin proteins like GSDMD, which can permeabilize the plasma membrane leading to the release of proinflammatory signals. While both ferroptosis and pyroptos","journal":"Frontiers in Physiology","year":2025,"id":557415,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9611,"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":597451,"name":"Robert N. Correll","orcid":"0000-0003-1453-9675","position":1,"is_corresponding":false},{"id":316212,"name":"Qinghang Liu","orcid":null,"position":2,"is_corresponding":false},{"id":294077,"name":"Jennifer Q. Kwong","orcid":"0000-0001-9867-7658","position":0,"is_corresponding":true}],"reference_count":7,"raw_metadata":null,"created_at":"2026-07-19T02:55:17.435961Z","pmid":"40161973","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":[]}