2. Academic Validation
  3. PGAM1-dependent VDAC1 oligomerization disrupts mitochondrial quality control to drive doxorubicin cardiotoxicity via the cGAS-STING-ferroptosis axis

PGAM1-dependent VDAC1 oligomerization disrupts mitochondrial quality control to drive doxorubicin cardiotoxicity via the cGAS-STING-ferroptosis axis

  • Free Radic Biol Med. 2026 Apr:247:71-94. doi: 10.1016/j.freeradbiomed.2026.01.065.
Yukun Li 1,  Sicheng Zheng 2,  Haowen Zhuang 3,  Ji Wu 4,  Junyan Wang 5,  Xing Chang 6
Affiliations

Affiliations

  • 1 Department of Cardiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China; Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100012, China.
  • 2 Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, 110032, China.
  • 3 School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China.
  • 4 Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China.
  • 5 School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China. Electronic address: [email protected].
  • 6 Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China. Electronic address: [email protected].
PMID: 41651300 DOI: 10.1016/j.freeradbiomed.2026.01.065
Abstract

Objectives: Doxorubicin (Dox) is a potent chemotherapeutic agent whose clinical use is limited by severe cardiotoxicity. The underlying molecular mechanisms remain incompletely understood. This study aimed to investigate the role of the phosphoglycerate mutase 1 (PGAM1)/voltage-dependent anion channel 1 (VDAC1) axis in early-stage Dox-induced cardiotoxicity, focusing on its impact on mitochondrial quality control (MQC), endoplasmic reticulum (ER) stress, and the subsequent activation of innate immune signaling.

Methods: We established a short-term cumulative Dox-induced cardiomyopathy model using wild-type and cardiomyocyte-specific PGAM1 knockout (PGAM1-CKO) mice. Cardiac function was assessed by echocardiography. In vitro experiments were performed on neonatal mouse cardiomyocytes (NMCMs) and HL-1 cells. Molecular techniques including Western blotting, immunofluorescence, co-immunoprecipitation, and quantitative PCR were used to dissect the signaling pathway. Key pathway components were validated using specific pharmacological inhibitors and activators.

Results: Dox treatment significantly upregulated PGAM1 expression in cardiomyocytes. PGAM1-CKO mice were protected from Dox-induced cardiac dysfunction, fibrosis, and inflammation. Mechanistically, Dox-induced PGAM1 promoted the pathological oligomerization of VDAC1. This PGAM1-VDAC1 interaction triggered the collapse of MQC and induced ER stress, leading to the leakage of mitochondrial DNA (mtDNA) into the cytosol. The released cytosolic mtDNA subsequently activated the cGAS-STING innate immune pathway, which we identified as a critical upstream driver of cardiomyocyte Ferroptosis. Pharmacological induction of VDAC1 oligomerization or STING activation abolished the cardioprotective effects observed in PGAM1-CKO mice.

Conclusion: Our findings reveal a novel PGAM1/VDAC1 signaling axis that triggers early Dox-induced cardiotoxicity. This axis disrupts mitochondrial homeostasis, leading to mtDNA release, which activates the cGAS-STING pathway and ultimately culminates in cardiomyocyte Ferroptosis. Targeting the PGAM1/VDAC1 interaction presents a promising therapeutic strategy to mitigate Dox-induced cardiac injury.

Keywords

Doxorubicin cardiotoxicity; Ferroptosis; Mitochondria quality surveillance; PGAM1/VDAC1 axis; cGAS-STING pathway.

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