Curcumin alleviates BPAF-induced ferroptosis in caprine endometrial epithelial cells through inhibition of endoplasmic reticulum stress and autophagy.

Abstract

Bisphenol AF (BPAF) is widely used as a substitute for bisphenol A (BPA) in the plastics industry. However, it is known to cause reproductive toxicity in both humans and animal models. Curcumin, a polyphenolic compound from turmeric, is known for its potent anti-inflammatory and antioxidant effects. We previously showed that curcumin alleviates BPAF-induced apoptosis in caprine endometrial epithelial cells (EECs). However, the underlying mechanisms of BPAF toxicity remain unclear. The aim of this study was to investigate whether ferroptosis contributes to BPAF-induced injury in EECs and to assess the protective role of curcumin. We demonstrate that BPAF triggers ferroptosis in EECs: ferroptosis-related factors (COX2, FACL4, and NCOA4) were upregulated, and GSH content was increased. These effects were significantly reversed by the ferroptosis inhibitor Fer-1, which restored cell viability and reduced MDA accumulation. Mechanistically, BPAF-induced ferroptosis was autophagy-dependent, as evidenced by upregulated ATG5, Beclin1, and LC3, and enhanced autophagic flux. Inhibition of autophagy by CQ significantly attenuated ferroptosis and improved cell viability. Furthermore, ER stress acted as an upstream regulator, as its inhibitor 4-PBA alleviated both autophagy and ferroptosis. BPAF also disrupted cellular iron homeostasis by promoting NCOA4-mediated ferritinophagy, resulting in intracellular iron accumulation. Curcumin pretreatment alleviated BPAF-induced ferroptosis by suppressing ferritinophagy and restoring iron homeostasis. Moreover, activation of the PI3K/AKT/mTOR and Nrf2/HO-1 pathways may exert protective effects by suppressing autophagy and lipid peroxidation. In conclusion, this study indicates that ferroptosis is a key mechanism underlying BPAF-induced cytotoxicity in EECs. Curcumin protects against this damage by inhibiting ER stress and autophagy, providing a potential therapeutic strategy for BPAF-related uterine diseases.

Key Findings

• BPAF induces ferroptosis in caprine endometrial epithelial cells by upregulating ferroptosis-related factors and increasing GSH content.
• Ferroptosis triggered by BPAF is autophagy-dependent and regulated upstream by endoplasmic reticulum stress.
• Curcumin alleviates BPAF-induced ferroptosis by inhibiting ER stress, autophagy, and ferritinophagy, and activating PI3K/AKT/mTOR and Nrf2/HO-1 pathways.

Clinical Significance

Citation

Liu Ming, Gao Cheng-Fang, Wang Jing-Jinget al.. Curcumin alleviates BPAF-induced ferroptosis in caprine endometrial epithelial cells through inhibition of endoplasmic reticulum stress and autophagy. Ecotoxicology and environmental safety. 2026-Jun-15.