Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

CRISPR-Based Screening of FDA-Approved Drugs for NRF2 Activation: A Novel Approach to Discover Therapeutics for Non-Alcoholic Fatty Liver Disease

Version 1 : Received: 5 June 2023 / Approved: 6 June 2023 / Online: 6 June 2023 (08:59:42 CEST)

A peer-reviewed article of this Preprint also exists.

Li, J.; Arest, S.; Olszowy, B.; Gordon, J.; Barrero, C.A.; Perez-Leal, O. CRISPR/Cas9-Based Screening of FDA-Approved Drugs for NRF2 Activation: A Novel Approach to Discover Therapeutics for Non-Alcoholic Fatty Liver Disease. Antioxidants 2023, 12, 1363. Li, J.; Arest, S.; Olszowy, B.; Gordon, J.; Barrero, C.A.; Perez-Leal, O. CRISPR/Cas9-Based Screening of FDA-Approved Drugs for NRF2 Activation: A Novel Approach to Discover Therapeutics for Non-Alcoholic Fatty Liver Disease. Antioxidants 2023, 12, 1363.

Abstract

With the rising prevalence of obesity, Non-Alcoholic Fatty Liver Disease (NAFLD) now affects 20-25% of the global population. NAFLD, a progressive condition associated with oxidative stress, can result in cirrhosis and liver cancer in 10% and 3% of patients suffering NAFLD, re-spectively. Therapeutic options are currently limited, emphasizing the need for novel treatments. In this study, we examined the potential of activating the transcription factor NRF2, a crucial player in combating oxidative stress, as an innovative approach to treating NAFLD. Utilizing a CRISPR-engineered human cell line, we were able to monitor the expression of heme oxygenase-1 (HMOX1), an NRF2 target, using a Nanoluc luciferase tag. Our model was validated using a known NRF2 activator, after which we screened 1200 FDA-approved drugs, unearthing six compounds (Disulfiram, Thiostrepton, Auranofin, Thimerosal, Halofantrine, and Vorinostat) that enhanced NRF2 activity and antioxidant response. These compounds demonstrated protec-tive effects against oxidative stress and lipid accumulation in vitro. Our study underscores the utility of CRISPR tagging with Nanoluc luciferase in identifying potential NRF2 activators, pav-ing the way for potential NAFLD therapeutics.

Keywords

NRF2; NAFLD; HMOX1; CRISPR, Oxidative Stress; Fatty Liver Disease

Subject

Medicine and Pharmacology, Medicine and Pharmacology

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