The melatonin-FTO-ATF4 signaling pathway protects granulosa cells from cisplatin-induced chemotherapeutic toxicity by suppressing ferroptosis.

PURPOSE

In cisplatin-induced premature ovarian failure (POF) mice, granulosa cells showed a high level of ferroptosis. Previous research has indicated that the fat mass and obesity-associated protein/activating transcription factor 4 (FTO/ATF4) axis was involved in the regulation of ferroptosis. The purpose of this study was to explore the role of the FTO/ATF4 axis in cisplatin-induced ferroptosis in granulosa cell.

METHODS

The extent of ferroptosis was assessed by transmission electron microscopy (TEM) and ROS, GPX, GSH, and MDA assays. Western blotting was used to evaluate the protein expression levels of ferroptosis-related molecules. Ferroptosis activator and inhibitor were also used.

RESULTS

We found that ferroptosis increased in a concentration-dependent manner in cisplatin-induced injured granulosa cells, accompanied by the downregulation of FTO. In addition, gain- and loss-of-function studies showed that FTO affects ferroptosis in injured cells by regulating ATF4 expression. Ferrostatin-1 inhibited the effect of FTO downregulation on injured granulosa cells ferroptosis, and erastin reversed the protective effect of FTO on ferroptosis in injured granulosa cells. Finally, melatonin was used, and we found that melatonin reduced ferroptosis in cisplatin-induced injured granulosa cells by upregulating FTO expression.

CONCLUSION

Our study demonstrated that cisplatin induced granulosa cell ferroptosis by downregulating the expression of FTO. ATF4 was identified as a downstream target of FTO, and overexpression of ATF4 reversed the effects of decreased FTO on ferroptosis. Additionally, melatonin mitigates the cytotoxic effects of cisplatin by upregulating FTO expression. The melatonin-FTO-ATF4 signaling pathway plays a vital role in the treatment of cisplatin-induced POF.