Emodin retards renal cyst progression in ADPKD by inhibiting cell proliferation and decreasing oxidative stress

Autosomal dominant polycystic kidney disease (ADPKD) is a common monogenic genetic disease characterized by bilateral renal cyst formation and enlargement. The purpose of this study was to explore the therapeutic effects of emodin, which is a key active constituent of traditional Chinese herbal medicine Rhubarb, on ADPKD and its underlying mechanisms. Herein, we found emodin significantly inhibited renal cyst progression in ADPKD. RNA-sequencing analysis and network pharmacological analysis indicated that emodin may exert its therapeutic effects by modulating cell proliferation and oxidative stress, in which the Wnt and Nrf2 related signaling pathways probably played important roles. These findings were subsequently verified. Emodin was shown to downregulate cell proliferation and oxidative stress levels, inhibit the proliferation-associated Wnt/β-catenin signaling pathway, and activate the antioxidant Nrf2/GPX4 signaling pathway. Furthermore, we found that the Wnt pathway exerted an inhibitory effect on Nrf2/GPX4 axis upstream. Through inhibition of the Wnt pathway, emodin may relieve its suppression of Nrf2/GPX4 axis, ultimately achieving dual modulation of proliferation and oxidative stress. RNA-sequencing analysis also indicated that Wnt7a was the most significantly altered Wnt pathway-related gene following emodin treatment in ADPKD. We confirmed that emodin reduced both the mRNA and protein levels of Wnt7a. Emodin also potentially acted as a direct binder to Wnt7a, this might be the upstream mechanism by which it modulated the Wnt pathway. Overall, our study suggested that emodin may serve as a potential therapeutic compound for ADPKD treatment.