Chicoric acid advanced PAQR3 ubiquitination to ameliorate ferroptosis in diabetes nephropathy through the relieving of the interaction between PAQR3 and P110α pathway

ABSTRACT

Purpose

This study aimed to examine the impact of CA on DN and elucidate its underlying molecular mechanisms of inflammation.

Methods

We fed C57BL/6 mice injected with streptozotocin to induce diabetes. In addition, we stimulated NRK-52E cells with 20 mmol/L d-glucose to mimic the diabetic condition.

Results

Our findings demonstrated that CA effectively reduced blood glucose levels, and improved DN in mice models. Additionally, CA reduced kidney injury and inflammation in both mice models and in vitro models. CA decreased high glucose-induced ferroptosis of NRK-52E cells by inducing GSH/GPX4 axis. Conversely, the ferroptosis activator or the PI3K inhibitor reversed positive effects of CA on DN in both mice and in vitro models. CA suppressed PAQR3 expression in DN models to promote PI3K/AKT activity. The PAQR3 activator reduced the positive effects of CA on DN in vitro models. Moreover, CA directly targeted the PAQR3 protein to enhance the ubiquitination of the PAQR3 protein.

Conclusion

Overall, our study has uncovered that CA promotes the ubiquitination of PAQR3, leading to the attenuation of ferroptosis in DN. This effect is achieved through the activation of the PI3K/AKT signaling pathways by disrupting the interaction between PAQR3 and the P110α pathway. These findings highlight the potential of CA as a viable therapeutic option for the prevention of DN and other forms of diabetes.

Graphical abstract

Cichoric acid (CA) extract of Dandelion advanced PAQR3 expression to ameliorate ferroptosis in DN by activating the PI3K/AKT signaling pathways. Importantly, CA advanced PAQR3 ubiquitination to restore PI3K/AKT signaling through the relieving the interaction between PAQR3 and P110α pathway.

KEYWORDS:

• Cichoric acid
• ferroptosis
• diabetes nephropathy
• PAQR3
• ubiquitination

Acknowledgments

This work was supported by National Natural Science Foundation of China (811731333); Key Natural Science Projects of the Department of Education of Anhui province (2022AH051239, 2023AH051767); Talent Introduction Program of Yijishan Hospital of Wannan Medical College (YR202005); Science and Technology Innovation Team of Yijishan Hospital of Wannan Medical College (YPF2019016, YR20230105), and Key projects of Wannan Medical (WK2021ZF11, KY23740650). Thanks to the central laboratory for its support to this research.

Disclosure statement

We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.

Authors’ contribution

Zhichen Pu and Yong Liu conceived the study, designed the study and prepared the manuscript. Yong Liu and Jiajun Zhou conducted the experiments and data analysis, involved in preparation of the figures and manuscript. All data were generated in-house, and no paper mill was used. All authors agree to be accountable for all aspects of work ensuring integrity and accuracy.

Abbreviations

DN	=	Diabetic nephropathy
CA	=	Cichoric acid
P AQR3	=	Progestin and adipo Q acceptor 3,
GPX4	=	glutathione peroxidase 4
PI3K	=	Phosphatidylinositol-4,5-bisphosphate 3-kinase
Akt	=	protein kinase B
Nrf2	=	Nuclear factor E2-related factor 2
HFD	=	high-fat diet
STZ	=	streptozotocin
Qpcr	=	Quantitative polymerase chain reaction
CCK8	=	Cell counting kit‑8
MST	=	Microscale thermophoresis
TSA	=	Thermal shift assay
CETSA	=	cellular thermal shift assay
co-IP	=	co-immunoprecipitation

Additional information

Funding

The work was supported by the National Natural Science Foundation of China [811731333].