Sex shapes radiation lung injury and drug response in rat study

Male and female rats respond differently to radiation-induced lung injury, and the three candidate radioprotective drugs tested against it — enalapril, metformin and pentoxifylline — did not behave uniformly across the sexes, according to a preclinical study published in BMC Cancer. In the irradiation-only group, male rats showed more severe peribronchial lymphoid infiltration than females (p = 0.010), and molecular activation peaked at week 12, when males had higher TGFβ1 and VEGF expression than females (p = 0.009 for both). By week 24, males displayed more evident chronic fibrovascular injury, suggesting a more pronounced injury phenotype after localized right-lung irradiation.

The study involved 130 Sprague-Dawley rats divided into Sham, RT-only, Enalapril + RT, Metformin + RT, or Pentoxifylline + RT groups according to their sex. Rats in the irradiation groups received a single dose of 15 Gy to the right lung. Treatments began one week before irradiation and continued throughout the follow-up period, and animals were sacrificed at the end of weeks 6, 12, or 24 for molecular and histopathological analyses. TGFβ1 and VEGF mRNA expression was measured by qRT-PCR, and histopathology was assessed separately in the irradiated right lung and the non-irradiated contralateral left lung using semi-quantitative scoring and alveolar wall thickness measurement.

The treatment results diverged sharply by drug, sex and lung compartment. Metformin significantly reduced chronic alveolar wall thickness in males at week 24 (p = 0.003), a selective male-specific effect on structural remodeling. Pentoxifylline showed the broadest treatment-related pattern, with significant reductions in chronic peribronchial lymphoid infiltration in males (p = 0.030) and delayed contralateral neutrophil infiltration (p = 0.013) and edema (p = 0.038) in females. Enalapril showed mainly early, non-significant inflammatory trends — including neutrophilic and vascular changes, particularly in female rats — without consistent statistically significant effects on later structural endpoints.

The authors note that selective changes seen in the non-irradiated contralateral lung should be interpreted cautiously, as they may be consistent with delayed abscopal-like or systemic bystander responses involving inflammatory and microvascular components. Because the work was conducted in a rat model of localized right-lung irradiation, the findings are preclinical and cannot be directly extrapolated to patients receiving thoracic radiotherapy. Nevertheless, the researchers argue that biological sex appeared to modify both radiation-induced injury patterns and treatment responsiveness, and they call for a more tailored approach in preclinical radioprotection research — one in which treatment effects are evaluated according to biological sex, post-irradiation timing, lung compartment, and the dominant histopathological endpoint, rather than assuming a uniform response across all injury components.

Subject of Research: Sex-dependent differences in radiation-induced lung injury and drug response in rats

Article Title: The impact of biological sex on the efficacy of enalapril, metformin and pentoxifylline in radiation-induced lung injury

Article References: Coşar, R., Koçak, Z., Taştekin, E., Süt, N., Tabakçıoğlu, K., Parlar, Ş., Özgüven, Y., Dertli, M. H., Yalçın, A., Batu, S., Özben, H., Selvi, K., Demir, M., Demir, S., Kaynar, E., Koçmar, O., & Uşar, M. (2026). The impact of biological sex on the efficacy of enalapril, metformin and pentoxifylline in radiation-induced lung injury. BMC Cancer. https://doi.org/10.1186/s12885-026-17112-w

Image Credits: AI Generated

DOI: 10.1186/s12885-026-17112-w

Keywords: radiation-induced lung injury, biological sex, enalapril, metformin, pentoxifylline, TGFβ1, VEGF, radioprotection, preclinical study, rats, fibrosis, thoracic radiotherapy