CMPK2–mtDNA Axis Drives Doxorubicin Heart Damage, Study Finds

Doxorubicin, a widely used chemotherapy drug, is limited by dose-dependent damage to the heart, and the mechanisms connecting mitochondrial dysfunction to cardiac inflammation have remained poorly defined. A new mouse study published in Cellular & Molecular Biology Letters identifies the mitochondrial nucleotide metabolic enzyme CMPK2 as a central mediator of this cardiotoxicity and reports that the natural coenzyme flavin adenine dinucleotide (FAD) can block the damaging pathway in mice without reducing the drug’s antitumor efficacy.

Using cardiomyocyte-specific CMPK2 knockout and overexpression mouse models, along with AAV9-mediated cardiac gene delivery in vivo and molecular assays in vitro, the researchers found that CMPK2 expression was significantly upregulated in doxorubicin-injured hearts. Overexpression of CMPK2 in cardiomyocytes worsened doxorubicin-induced cardiac dysfunction, atrophy, oxidative stress and fibrosis, while knockdown of the enzyme attenuated these pathological changes. Tumor-bearing mouse models were used to check whether manipulating the pathway affected chemotherapy effectiveness.

Mechanistically, the study reports that CMPK2 drove oxidative mitochondrial DNA damage and leakage of that DNA into the cytosol, which subsequently triggered activation of the NLRP3 inflammasome, an inflammatory signaling complex. The team also identified the transcription factor STAT1 as an activator of CMPK2 gene expression, linking inflammatory transcriptional regulation to mitochondrial DNA release in a single pathological axis.

Importantly, the researchers found that flavin adenine dinucleotide directly bound to CMPK2 and blocked its downstream signaling. FAD administration mitigated doxorubicin-induced cardiac injury in mice without compromising the drug’s antitumor efficacy, suggesting a selectively cardioprotective approach. The authors conclude that targeting the CMPK2–mtDNA–NLRP3 axis with FAD represents a promising strategy in cardio-oncology, though the findings are preclinical and based on mouse models and in vitro assays, so human efficacy remains to be established.

Subject of Research: The role of the CMPK2–mitochondrial DNA–NLRP3 axis in doxorubicin-induced cardiotoxicity and its inhibition by flavin adenine dinucleotide in mice.

Article Title: The CMPK2–mtDNA axis mediates doxorubicin cardiotoxicity: mechanistic links to STAT1 transcription and FAD-mediated inhibition

Article References: Feng, Z., Lin, L., Yang, Y., Sun, X., Yang, X., Zhang, N., Dong, Y., & Xie, Y. (2026). The CMPK2–mtDNA axis mediates doxorubicin cardiotoxicity: mechanistic links to STAT1 transcription and FAD-mediated inhibition. Cellular & Molecular Biology Letters. https://doi.org/10.1186/s11658-026-01025-4

Image Credits: AI Generated

DOI: 10.1186/s11658-026-01025-4

Keywords: doxorubicin, cardiotoxicity, CMPK2, mitochondrial DNA, NLRP3 inflammasome, STAT1, flavin adenine dinucleotide, cardio-oncology, mouse models, mitochondrial dysfunction, mtDNA, axis