Received July 12, 2025
Accepted February 20, 2026

Objective: This study investigates the effects of Piperine (PIP) on doxorubicin (DOX)-induced changes in mouse ovarian follicles, stromal cells, collagen fibers, and mRNA expression of nuclear factor erythroid 2-related factor (NRF2), superoxide dismutase (SOD), and catalase (CAT). Methods: The mice were randomly divided into seven groups. In the first three groups, they received saline (1), both DOX and N-acetylcysteine (2), or DOX only (3). In groups 4 and 5, mice were treated with DOX in combination with 0.1 or 10.0 mg/kg PIP. In groups 6 and 7, mice received 0.1 or 10.0 mg/kg PIP alone. After 10 days, ovaries were collected and used to evaluate follicular morphology and growth, collagen fibers, stromal cells, and mRNA for NRF2, SOD, and CAT. Results: Mice treated with DOX showed reduced percentage of normal follicles, but the combination of DOX with PIP or NAC prevented this effect, maintaining follicle integrity similar to untreated animals. Ovaries of mice treated with PIP alone had similar percentage of normal follicles compared to control group. Additionally, the association of DOX and PIP preserved collagen levels similar to control, while PIP or NAC alone did not influence collagen distribution. Ovaries of mice treated with both DOX and NAC showed a reduction in stromal cells, but those treated with both DOX and PIP maintained the levels of collagens similar to control. Conclusions: The DOX and PIP preserved the integrity of follicles and collagen fibers in mouse ovaries, which opens a new possibility to protect primordial follicles during chemotherapy.