January 10, 2026Journal of the American Heart Association0 citationsOpen Access

Superoxide Mediates Radiation‐Induced Cardiac Injury and Activates the Canonical Transforming Growth Factor‐Beta Signaling Pathway

Q: What does this research mean for the field?

Ucosopasem manganese (RUC) significantly improves overall survival and cardiac function while reducing fibrosis and TGF‐β pathway activation after radiation injury in mice. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

KMKranti A. MapuskarUniversity of Iowa Hospitals and Clinics CPCasey PulliamUniversity of Iowa ATAnn Tomanek‐Chalkley

Key Result

Ucosopasem manganese (RUC) significantly improved overall survival and cardiac function while reducing fibrosis and TGF‐β pathway activation after radiation injury in mice.

Key Points

The aim is to understand how superoxide mediates radiation-induced cardiac injury and its effects on mitochondrial function.
Used a cardiac targeted radiation injury model on C57BL/6J female mice.
Mice received a single exposure of 16 Gy radiation followed by treatment with an SOD mimetic, RUC.
Cardiac function was assessed via echocardiography over a 9-month period.
CTI cardiovascular toxicities were observed in all irradiated mice.
RUC treatment significantly increased overall survival and improved cardiac function.
RUC reduced cardiac fibrosis and the activation of the TGF-beta/Smad pathway.

Structured PICO

Does rucosopasem manganese prevent radiation-induced cardiac injury and improve survival in a murine model of cardiac targeted radiation injury?

Population

10- to 12-week-old female C57BL/6J mice (n=65) subjected to a cardiac targeted radiation injury (CTI) model (single 16 Gy dose).

Intervention

Rucosopasem manganese (RUC) 12 mg/kg intraperitoneal starting 1 hour before CTI, daily for 7 days following CTI, and weekly thereafter until euthanasia at 9 months.

Comparator

Sham irradiation with intraperitoneal vehicle, and CTI alone with intraperitoneal vehicle.

Outcome

Overall survival and cardiopulmonary implications (cardiac function, mitochondrial bioenergetics, and cardiac fibrosis) over 9 months.

In a murine model, the superoxide dismutase mimetic rucosopasem manganese significantly improved survival and attenuated radiation-induced cardiac fibrosis and dysfunction by antagonizing the TGF-β/Smad pathway.

Main Result

Absolute Event Rate: 0% vs 0%

Abstract

Background Therapeutic ionizing radiation is a standard treatment modality for thoracic cancers that may affect surrounding normal tissues, including the cardiovascular system. The increasing recognition of mitochondrial health in cellular responses to oxidative stress, particularly in ionizing radiation‐induced cardiac implications, highlights mitochondria as a critical target for therapeutic interventions. Optimizing mitochondrial function to attenuate ionizing radiation‐induced cardiac pathology necessitates balancing killing cancer cells with sparing nonmalignant tissues. Methods Using a cardiac targeted radiation injury (CTI) model of injury, C57BL/6J female mice were exposed to a single 16 Gy dose and treated with an SOD (superoxide dismutase) mimetic, ucosopasem manganese (RUC) starting 1 hour before CTI, continued daily for 1 week post CTI, and once per week thereafter until euthanasia to investigate cardiopulmonary implications over 9 months. Results CTI cardiovascular toxicities were observed in all irradiated mice. RUC significantly increased overall survival and alleviated CTI‐induced changes in cardiac function as assessed by cardiac echocardiography. Persistent changes in mitochondrial oxidative phosphorylation proteins and tricarboxylic acid cycle enzymes were notably attenuated following RUC treatment. Interestingly, RUC reduced both CTI‐induced cardiac fibrosis and the activation of the TGF‐β/Smad (transforming growth factor‐beta/suppressor of mothers against decapentaplegic transcription factor family) pathway. Conclusions This study presents a novel role for selective superoxide dismutase mimetics, such as RUC, in protecting against CTI‐induced cardiovascular toxicities. As RUC dismutates superoxide, the results suggest superoxide plays a key part in the modulation of mitochondrial oxidative phosphorylation, activation of the canonical TGF‐β/Smad pathway, and ionizing radiation cardiovascular side effects. These findings suggest an association between RUC treatment and TGF‐β pathway antagonism that requires additional mechanistic validation.

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