{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T00:45:46Z","timestamp":1787705146446,"version":"build-2784847793"},"reference-count":120,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T00:00:00Z","timestamp":1782086400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Heart failure with preserved ejection fraction (HFpEF) is a systemic inflammatory disease that affects multiple organs. However, the integration of different comorbid stress factors into a persistent and organ-specific inflammatory network remains unclear. Under the background of HFpEF, mitochondrial DNA (mtDNA) may not only play a role as a damage-associated molecular pattern (DAMP), but also act as a cross-organ inflammatory signal, linking the comorbid-driven mitochondrial stress with endothelial dysfunction, myocardial remodeling, and extracardiac organ involvement. Under the influence of HFpEF-related stress factors, including aging, obesity, diabetes, hypertension, and renal dysfunction, mtDNA may undergo oxidation and structural remodeling and be released in the form of free DNA, extracellular vesicle (EV)-related DNA, or neutrophil extracellular trap-related DNA. These mtDNA signals may activate the nucleic acid sensing pathways mediated by TLR9 and cGAS-STING, and promote the activation of downstream NLRP3 inflammasomes in endothelial cells, cardiomyocytes, fibroblasts, immune cells, and extracardiac tissues, thereby promoting IL-6\/TNF production, type I interferon signaling, inflammasome activation, and self-amplifying inflammatory circuits related to the progression of HFpEF. Within this framework, HFpEF can be understood as a cross-organ network reconfiguration state, where mtDNA-related inflammatory signals may lead to abnormal information flow, especially in the internal phenotype characterized by metabolic stress, age-related mitochondrial damage, renal dysfunction, and systemic inflammation. The coupling between mtDNA generation, transmission, and decoding may amplify endothelial dysfunction, myocardial stiffness, fibrosis, and phenotypic-specific inflammatory remodeling; however, these processes occur within a broader pathological biology background of HFpEF, which also includes mechanisms independent of mtDNA, such as impaired NO\u2013cGMP\u2013PKG signaling, low phosphorylation of myosin, vascular stiffness, renal dysfunction, neurohumoral activation, and extracellular matrix remodeling. Therefore, this article proposes that mtDNA efflux is an inflammation amplifier that depends on the phenotype and disease stage, rather than being a universal or unique mechanism for explaining all HFpEF phenotypes. The existing evidence does not yet prove that mtDNA efflux is the main causal driver of HFpEF; instead, its position in the temporal sequence and causal relationship still needs to be verified in longitudinal studies and intervention studies specific to HFpEF.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1866184","type":"journal-article","created":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T04:36:43Z","timestamp":1782103003000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Mitochondrial DNA efflux as a potential amplifier of systemic inflammatory network rewiring in heart failure with preserved ejection fraction"],"prefix":"10.3389","volume":"17","author":[{"given":"Xingwei","family":"Zhao","sequence":"first","affiliation":[{"name":"Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University","place":["Luzhou, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengyu","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, The Affiliated Hospital, Southwest Medical University","place":["Luzhou, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiulin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The Affiliated Hospital of Southwest Medical University","place":["Luzhou, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Yu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University","place":["Luzhou, Sichuan, China"]},{"name":"Department of Cardiology, The Affiliated 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