Organ-specific redox imbalances in spinal muscular atrophy mice are partially rescued by SMN antisense oligonucleotides.

Spinal muscular atrophy (SMA) is caused by a deficiency in survival motor neuron (SMN) protein; redox imbalance and oxidative stress are also implicated. Protein S-glutathionylation (PSSG) is a reversible redox modification that protects cysteines from irreversible oxidation and regulates protein function. Here, we report stage- and tissue-dependent defects in PSSG levels, accompanied by tissue-specific alterations in the expression of glutathione-related enzymes in Taiwanese SMA mice at early and late symptomatic stages. Importantly, we also provide evidence linking glutathione homeostasis defects with ferroptosis. Finally, partial restoration of SMN by antisense oligonucleotides selectively modulates these abnormalities in a tissue-dependent manner. Our findings suggest S-glutathionylation dysregulation as a novel SMA hallmark and highlight persistent redox imbalance as a therapeutic target beyond SMN restoration. Impact statement This study provides a multi-organ analysis of redox imbalance in spinal muscular atrophy, revealing systemic loss of protein S-glutathionylation in a stage- and tissue-dependent manner. By identifying the heart as particularly redox-vulnerable, this work refines understanding of oxidative stress beyond motor neurons and informs tissue-aware therapeutic evaluation.