Resveratrol: Great potential for alleviating di-2-ethylhexyl phthalate (DEHP)-induced testicular ferroptosis via the SIRT1-HIF-1α axis.

BACKGROUND/

OBJECTIVES

Di-2-ethylhexyl phthalate (DEHP) is a universally used plasticizer and EDCs. Our previous studies verified that prolonged contact with DEHP induced detrimental impacts on reproductive physiology. Resveratrol (RES), a polyphenolic compound predominantly concentrated in Vitis vinifera epidermis, exhibits multifaceted pharmacological properties. The purpose of this study was to investigate whether RES can alleviate testicular injury caused by DEHP, and to investigate its possible mechanism.

METHODS

The experimental design comprised 4 randomized groups of male SD rats: Control group: each animal was given corn oil and saline. DEHP group: the animals received DEHP (500 mg/kg/day) and saline. DEHP and RES group: the animals received DEHP (500 mg/kg/day) and RES (60 mg/kg/day). RES group: the animals received corn oil and RES (60 mg/kg/day).

RESULTS

In vivo, RES alleviated DEHP-induced testicular ferroptosis by upregulating SIRT1 and enhancing its interaction with HIF-1α. This mechanism suppressed mitophagy, decreased Fe²⁺and ROS release, and inhibited lipid peroxidation. TM4 cell experiments confirmed these findings. Notably, SIRT1 knockdown inhibited the remission effect of RES on ferroptosis.

CONCLUSIONS

In summary, we demonstrated that RES mitigated testicular damage caused by DEHP by inhibiting ferroptosis through the SIRT1-HIF-1α axis. This investigation delineates novel molecular targets and mechanistic frameworks for developing therapeutic interventions against DEHP toxicity.