Now, a team of researchers from the University of Szeged in Hungary and the Medical University of Vienna in Austria has reported that a synthetic version of an embryo-derived peptide may protect the heart from radiation damage while potentially preserving, and even enhancing, the anti-cancer efficacy of radiotherapy. The peptide in question is preimplantation factor, or PIF, an evolutionarily conserved 15-amino-acid peptide secreted by viable mammalian embryos. In pregnancy, PIF plays a critical role in maternal tolerance of the fetal allograft, providing integrated local and systemic immune protection, transplant acceptance, and controlled cell and organ growth. It supports embryo implantation by modulating cell proliferation and apoptosis, and it exhibits immunomodulatory, anti-inflammatory, and regenerative properties. The lessons learned from pregnancy have been translated to non-pregnancy applications, including neurologic diseases, atherosclerosis, and radiation protection, and a synthetic PIF analog containing the same amino acid sequence as the native peptide has already shown protective effects against neuroinflammation, type 1 diabetes, Duchenne muscular dystrophy, and acute radiation syndrome.

In the new study, published in Frontiers in Cardiovascular Medicine, the researchers investigated whether synthetic PIF, or sPIF, could mitigate the development of radiation-induced heart disease in rats. Adult male Sprague-Dawley rats were allocated into three experimental groups: a vehicle-treated control group, a vehicle-treated radiotherapy group receiving a single focused dose of 50 Gy to the heart, and a radiotherapy group treated with sPIF. The animals were monitored at one, three, and fifteen weeks after irradiation, reflecting the acute, subacute, and chronic phases of radiation injury. Endpoint assessments included transthoracic echocardiography, histopathology, quantitative polymerase chain reaction, Western blotting, and ultra-high-performance liquid chromatography-tandem mass spectrometry in left ventricular samples. The sPIF was administered subcutaneously at 1 mg/kg, a dose selected based on previous dose-finding experiments and on preclinical models in which 0.1 to 1 mg/kg had maximum efficacy. Treatment began daily for the first two weeks and continued twice weekly thereafter, an approach adapted from previous episodic sPIF administration in experimental autoimmune encephalomyelitis models.

The results were striking. At week three, sPIF treatment markedly reduced left ventricular overexpression of the pro-inflammatory cytokines interleukin-1 and interleukin-6, as well as the pro-survival and anti-inflammatory signal transducer and activator of transcription 3, compared with the vehicle-treated control group. This early anti-inflammatory effect presumably enabled fibrosis prevention at fifteen weeks. At the same time, the sPIF-treated radiotherapy group exhibited marked reductions in left ventricular end-diastolic and end-systolic diameters compared with the vehicle-treated control or radiotherapy groups, accompanied by increased long-axis fractional shortening. The radiotherapy-induced diastolic dysfunction observed at week three, indicated by reduced mitral annulus velocity and elevated E/e’ ratio, was markedly reduced by sPIF treatment. By week fifteen, the vehicle-treated radiotherapy group had developed concentric left ventricular hypertrophy, with significantly increased septal, posterior, and anterior wall thicknesses and relative wall thickness, as well as prolonged isovolumic relaxation time and elevated Tei index, all indicating diastolic dysfunction. sPIF treatment partially reversed these irradiation-induced changes, reflected by significant reductions in wall thicknesses and relative wall thickness, improvement in left ventricular dimensions and fractional shortening, and normalization of diastolic functional parameters.

At the cellular level, the protective effects were equally evident. At week fifteen, cardiomyocytes in the vehicle-treated radiotherapy group showed significantly increased perimeter and cross-sectional area, confirming the development of compensatory hypertrophy. Notably, there were no marked differences in cardiomyocyte perimeters and cross-sectional areas between the sPIF-treated radiotherapy group and the vehicle-treated control group at week fifteen. Molecular analysis revealed that the vehicle-treated radiotherapy group had significantly reduced expression of the adult myosin heavy chain alpha-isoform, Myh6, and a markedly higher Myh7/Myh6 ratio, indicating molecular signs of left ventricular hypertrophy development. sPIF preserved healthy adult myosin heavy chain isoform content compared with the vehicle-treated radiotherapy group. The researchers also found that sPIF treatment significantly mitigated the radiotherapy-induced reduction of left ventricular sarcoendoplasmic reticulum calcium ATPase 2a isoform, or SERCA2a, protein level at week fifteen. More preclinical studies have found a significant inverse correlation between SERCA2a gene expression and isovolumic relaxation time, indicating impaired relaxation and a potential association with heart failure with preserved ejection fraction.

Beyond hypertrophy, sPIF treatment alleviated the radiotherapy-associated cardiac fibrosis. At week fifteen, sPIF significantly reduced left ventricular expression of connective tissue growth factor and protein levels of SMAD2/3, key mediators of the transforming growth factor-beta1 pathway considered the central molecular mechanism in radiation-induced cardiac fibrosis. sPIF also significantly decreased left ventricular fibrosis at week fifteen and mitigated overexpression of A-type natriuretic peptide, a myocardial stretch marker. The antioxidant properties of sPIF were reflected in significantly reduced nitrotyrosine levels, a marker of nitro-oxidative stress, in the left ventricles after sPIF treatment compared with the vehicle-treated radiotherapy group at week fifteen. The left ventricular riboflavin content, a cofactor of the antioxidant glutathione redox cycle, remained markedly higher in the sPIF-treated radiotherapy group compared with the vehicle-treated control group. The nicotinamide adenine dinucleotide levels were markedly higher in the sPIF-treated radiotherapy group at week fifteen compared to the time-matched vehicle-treated control groups, supporting antioxidant mechanisms by increasing glutathione levels and antioxidant enzyme activity.

The cardioprotective effects of sPIF were further validated in vitro. In H9c2 cardiomyoblasts, sPIF suppressed angiotensin II-induced hypertrophy, with the cell size of sPIF-treated cardiomyoblasts being significantly smaller compared to the angiotensin II-treated group. The co-treatment with sPIF markedly counterbalanced the reduced viability of H9c2 cardiomyoblasts exposed to hydrogen peroxide-induced oxidative stress. In human ventricular cardiac fibroblasts, sPIF treatment significantly reduced collagen-I and alpha-smooth muscle actin protein expression after exposure to transforming growth factor-beta1. Scratch assays revealed a biphasic influence of transforming growth factor-beta1 on cardiac fibroblast motility, with transient enhancement of migration in the early phase after scratching but marked delay in the later phases, reflecting its canonical induction of myofibroblast differentiation, stress fiber assembly, and excessive extracellular matrix deposition. sPIF significantly supported migration in the early phase and appeared to abrogate the late inhibitory action of transforming growth factor-beta1, suggesting a role in modulating fibroblast-driven repair while mitigating maladaptive fibrosis.

Perhaps most importantly for cancer patients, sPIF did not interfere with the anti-cancer efficacy of radiotherapy. In three different human breast carcinoma cell lines, MCF-7, T47D, and MDA-MB-231, none of the tested concentrations of sPIF increased cell proliferation within 72 hours. Moreover, sPIF intensified the anti-proliferative effect of radiotherapy in breast cancer cell lines compared to radiotherapy alone. This finding is in line with previously reported sPIF-induced anti-neoplastic effects and suggests that sPIF may serve as a potential dual cardioprotective and anti-proliferative agent. The researchers hypothesized that the enhanced acute inflammation induced by sPIF in the early phase might facilitate the elimination of tissue debris and contribute to the earlier start of adaptive mechanisms and wound healing processes, mainly due to the immunomodulatory effects of the peptide. By week fifteen, sPIF appeared to prevent chronic cell death and limit harmful remodeling in radiation-induced heart disease.

Mechanistically, sPIF primarily targets protein disulfide isomerase/thioredoxin and heat shock proteins, thereby reducing oxidative stress and protein misfolding and preventing cellular damage. These targeted protective mechanisms are key in addressing radiotherapy-induced organ damage. sPIF has been reported as a robust immunomodulator and cellular protector in acute radiation syndrome by binding to innate immune cells such as macrophages and neutrophils, suppressing inflammatory mediators such as tumor necrosis factor-alpha and inducible nitric oxide synthase, and promoting a tolerant, balanced immune profile. It regulates innate immunity by blocking voltage-gated potassium channels, thereby reducing overactivity of neutrophils and natural killer cells without broad immune depletion, and selectively tunes adaptive immunity by inhibiting pro-inflammatory pathways like IL-23 and IL-17a-mediated signaling, thereby reducing toxicity but preserving infection defense. Notably, sPIF has been tested in Fast Track FDA human clinical trials for autoimmune disease, demonstrating safety and the absence of adverse drug-drug interactions, and has received FDA orphan drug designation for acute radiation syndrome.

The authors recognize several limitations of the current study. Significant differences exist in the pathomechanisms of experimental and clinical radiation-induced heart disease, comprising species-, sex-, and age-related attributes, as well as the absence of tumors, atherosclerosis, and other cardiovascular risk factors. To avoid cycle- and hormone-dependent protective effects, the researchers opted to use only male rats. Moreover, the therapeutic effects of sPIF were tested in a healthy adolescent rat model, which represents an additional limitation. Single-dose irradiation models differ from clinical radiotherapy, which typically uses multiple smaller fractions, and single doses can exaggerate and accelerate tissue damage in preclinical models. The researchers acknowledge that findings from single-dose models might have limited translational relevance, although they note that in modern radiotherapy practice, very high doses are used in stereotactic radiosurgery, and their findings may also apply to that field. Animal models incorporating both sexes, mediastinal tumors or breast cancer, cardiovascular risk factors, comorbidities, and advanced age would more closely recapitulate the clinical setting of radiation-induced heart disease.

Despite these limitations, the study identified sPIF as a novel, promising, druggable candidate for preventing and improving the signs of radiation-induced heart disease. The researchers emphasize that the exact initiating targets and upstream signaling mechanisms of sPIF in radiation-induced heart disease remain unexplored, and that transforming growth factor-beta/SMAD signaling and SERCA2a preservation are correlative biomarkers rather than definitive proof of direct mechanisms. Future preclinical studies could clarify the cardioprotective and anti-neoplastic mechanisms of sPIF and its direct mechanistic links to nitro-oxidative stress, inflammation, fibrosis, and apoptosis in radiation-induced heart disease. Given its effectiveness in preclinical models, sPIF could be a valuable addition to cancer radiotherapy regimens and warrants further exploration of its safety and efficacy in human trials. For the growing population of cancer survivors living with the cardiovascular consequences of their life-saving treatment, the prospect of a pregnancy-derived peptide that shields the heart without weakening the anti-cancer beam represents a genuinely new direction in cardio-oncology.

Subject of Research: Cardio-Oncology

Article Title: Synthetic preimplantation factor ameliorates the severity of radiotherapy-induced heart disease in a rat model

Article References: Kovács, M. G., Antunes Goncalves, A. I., Varga, Z., Losonczi, R., Kupecz, K., Volford, D., Pósa, S. P., Minorics, R., Galla, Z., Zins, K., Sejben, A., Kriston, A., Kovács, F., Horváth, P., Monostori, P., Cserni, G., Zupkó, I., Podesser, B. K., Barnea, E. R., … Sárközy, M. (2026). Synthetic preimplantation factor ameliorates the severity of radiotherapy-induced heart disease in a rat model. Frontiers in Cardiovascular Medicine, 13, Article 1946843. https://doi.org/10.3389/fcvm.2026.1946843

Image Credits: AI Generated

DOI: 10.3389/fcvm.2026.1946843

Keywords: radiation-induced heart disease, synthetic preimplantation factor, cardioprotection, radiotherapy, cardio-oncology, cardiac fibrosis, diastolic dysfunction, left ventricular hypertrophy, nitro-oxidative stress, breast cancer, Synthetic, preimplantation