REVIEW article
Front. Immunol.
Sec. Inflammation
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1640748
Cell-free mitochondrial DNA as a pro-inflammatory agent in blood circulation: mechanisms, therapeutic implications, and clinical challenges in immune dysregulation
Provisionally accepted
- 1Affiliated Hospital of North Sichuan Medical College, Nanchong, China
- 2Nanchong Central Hospital Affiliated to North Sichuan Medical College, Nanchong, China
- 3Chengdu Qingbaijiang District People's Hospital, Chengdu, China
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Circulating cf-mtDNA has emerged as a dual-functional entity in human pathophysiology, serving not only as a disease biomarker but also as a potent innate immune activators through its molecular pattern recognition. Extracellular mtDNA engages PRRs, triggering dysregulated pro-inflammatory signaling in multiple cell lineages. Elevated mtDNA in circulation correlate with pathogenesis of autoimmune disorders, infectious diseases, critical illnesses, neurological disorders, and hematological abnormalities. Therapeutic strategies combining mtDNA monitoring with inhibitors targeting its release mechanisms and downstream pathways offer novel immunomodulatory potential. This review systematically examines the therapeutic nexus of blood-derived mtDNA in immune activation and disease progression. Here we aim to elucidate the intricate role of mtDNA in disease pathobiology while highlighting mitochondria's central position in human systemic homeostasis.
Keywords: Immunity, mitochondrial DNA, cell-free DNA, Blood Circulation, Mitochondria, extracellular vesicles
Received: 04 Jun 2025; Accepted: 08 Sep 2025.
Copyright: © 2025 Zhao, Wu, Liang and Yang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Yangyang Zhao, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.