Abstract

Mitophagy, the process of removing mitochondria through the autophagy–lysosome pathway, is crucial for maintaining cellular homeostasis. However, its regulatory mechanisms and pathological implications remain poorly understood. In our study, we revealed that decidual protein induced by progesterone (DEPP) plays a significant role in mitophagy through the DEPP–HIF-1α–BNIP3/NIX axis. Our findings indicate that interaction between DEPP and hypoxia-inducible factor 1-alpha (HIF-1α) enhances HIF-1α stability, thereby promoting the transcription of HIF-1 target genes. The enhanced protein stability of HIF-1α not only activates mitophagy by stimulating the transcription of BCL2-interacting protein 3 ( BNIP3 ) and BCL2-interacting protein 3-like ( BNIP3L ; also known as NIX ) mRNA but also influences cellular metabolic reprogramming by promoting the transcription of glycolysis-related genes. In conclusion, our findings suggest that DEPP may act as a potential regulator of mitophagy and HIF-1α, playing an important role in maintaining cellular metabolic and energy homeostasis.