Background:
Duchenne muscular dystrophy (DMD) is a severe X-linked neuromuscular disorder caused by dystrophin deficiency, leading to recurrent muscle injury, inflammation, and fibrosis. Despite advances in gene and steroid-based therapies, chronic inflammation remains a major driver of disease progression. Low-dose radiation therapy (LDRT), long used for benign inflammatory conditions such as arthritis and tendinopathies, has demonstrated potent immunomodulatory and anti-fibrotic properties when administered at sublethal doses (<1.0 Gy). Recent evidence suggests that LDRT may reprogram immune and stromal cells, providing a potential therapeutic avenue for DMD.
Objectives:
This hypothesis-driven study explores the mechanistic rationale for using LDRT as an adjunctive therapy in DMD. Specifically, we aim to evaluate whether controlled low-dose irradiation can attenuate chronic inflammation, suppress fibroblast activation, and restore redox balance in dystrophic muscle.
Results (Proposed Mechanisms and Experimental Framework):
We propose that LDRT exerts therapeutic effects through five interconnected mechanisms:
Macrophage polarization: Shifting macrophage phenotype from pro-inflammatory (M1) to anti-inflammatory (M2) via modulation of NF-κB and STAT6 pathways.
Fibrosis inhibition: Downregulation of TGF-β and CTGF signaling, reducing fibroblast proliferation and collagen deposition.
Redox restoration: Upregulation of antioxidant enzymes such as SOD and HO-1 to mitigate oxidative stress.
Vascular modulation: Enhancement of eNOS activity, improving perfusion and limiting leukocyte infiltration.
Immune-pain regulation: Damping of pro-inflammatory cytokines that contribute to neuroinflammation and neuropathic pain.
To validate this hypothesis, we outline a four-phase preclinical framework: (1) in vitro co-culture models to assess cytokine and fibroblast responses, (2) in vivo evaluation using mdx mice, (3) transcriptomic and systems biology analyses to map signaling networks, and (4) translational safety assessment for genotoxicity and optimal dosing.
Conclusions:
LDRT offers a scientifically grounded, non-pharmacologic strategy to modulate the inflammatory–fibrotic axis in DMD. By reprogramming macrophage activity and fibroblast behavior, it may preserve muscle function and complement existing gene and steroid-based therapies. Although the concept challenges conventional paradigms, it bridges radiobiology and neuromuscular scienc