Importantly, we explored a novel role of PGRN in maintaining mitochondrial homeostasis via PGRN-Sirt1-PGC-1α/FoxO1 signaling-mediated mitochondrial biogenesis and mitophagy in podocytes, suggesting that targeting mitochondrial function and cellular bioenergetics upstream of cellular damage by PGRN may provide unexpected opportunities for the treatment of DN. Here, FOXO1 is linked to liver dysplastic nodule.