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DDX3X/MAVS alleviates doxorubicin‑induced cardiotoxicity by regulating stress granules

Kaixiang Zhao1, Shaochen Wang1, Dandan Feng2

  • 1Department of Cardiology, The First Affiliated Hospital of Shandong First Medical University (Shandong Provincial Qianfoshan Hospital), Jinan, Shandong 250014, P.R China.

Molecular Medicine Reports
|June 27, 2025
PubMed

Insights

DEAD-box RNA helicase 3 X-linked (DDX3X) and mitochondrial antiviral signaling (MAVS) protect against doxorubicin-induced cardiotoxicity by regulating stress granules (SGs). This finding offers new insights into preventing heart damage from chemotherapy.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Biochemistry

Background:

  • Doxorubicin (Dox) is a widely used chemotherapy agent, but its use is limited by cardiotoxicity.
  • The precise molecular mechanisms underlying Dox-induced cardiotoxicity (DIC) are not fully understood.
  • Identifying protective factors against DIC is crucial for improving patient outcomes.

Purpose of the Study:

  • To investigate the role of DEAD-box RNA helicase 3 X-linked (DDX3X), mitochondrial antiviral signaling (MAVS), and stress granules (SGs) in Dox-induced cardiotoxicity.
  • To elucidate the molecular pathways connecting DDX3X, MAVS, and SGs in the context of DIC.
  • To determine if DDX3X, MAVS, and SGs can be targeted for therapeutic intervention against DIC.

Main Methods:

  • H9c2 cardiomyocytes were treated with doxorubicin.
  • Levels of DDX3X, MAVS, and SGs were assessed.
  • Pharmacological agents (arsenite, anisomycin) and genetic manipulations (knockdown, overexpression) were used to modulate SG formation and DDX3X activity.
  • Western blotting, reverse transcription-quantitative PCR, immunofluorescence, and flow cytometry were employed for analysis.

Main Results:

  • Dox treatment led to decreased levels of DDX3X, MAVS, and SGs in H9c2 cardiomyocytes.
  • Pretreatment with arsenite (SG enhancer) alleviated Dox-induced myocardial injury, while anisomycin (SG inhibitor) exacerbated it.
  • DDX3X knockdown/inhibition decreased SG expression, whereas DDX3X overexpression promoted SG generation.
  • MAVS knockdown inhibited SG assembly and reduced Bcl2 expression, indicating MAVS acts as a link between DDX3X and SGs.

Conclusions:

  • DDX3X mitigates Dox-induced cardiotoxicity through the regulation of stress granule formation.
  • MAVS acts as a crucial intermediary, connecting DDX3X to SG assembly and influencing anti-apoptotic pathways.
  • DDX3X, MAVS, and SGs represent key protective factors against Dox-induced cardiotoxicity and potential therapeutic targets.
Keywords:
DEAD‑box RNA helicase 3 X‑linkedapoptosisdoxorubicin‑induced cardiotoxicitymitochondrial antiviral signalingstress granules

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