Therapeutic target identification and validation for MASLD via patient transcriptome-driven in vivo genetic screening

• Main Author: Lee, Yi Jing
• Other Authors: Torsten Wuestefeld
• Format: Final Year Project
• Language: English
• Published: Nanyang Technological University 2024
• Subjects: Medicine, Health and Life Sciences
• Online Access: https://hdl.handle.net/10356/181532
• Institution: Nanyang Technological University

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is rising in prevalence over the years but current treatments such as Resmetirom are inadequate as remedy for most MASLD patients. With scarce liver sources available, liver regeneration offers a more sustainable approach, especially in end-stage MASLD when liver transplantation is the only option for recovery. However, liver regeneration is often impaired in the MASLD disease state. Therefore, in search of potential therapeutic target that offers liver regeneration capabilities, we used MASLD patient-transcriptomic data to facilitate in vivo screening of pooled-shRNA library on MASLD dysregulated genes, leading to the identification of Target 1. Thus, we further validate Target 1’s potential using in vitro assays. Results: Transient and stable knockdown of Target 1 increased migratory and proliferative properties of AML12 hepatocytes in favor of liver regeneration. Furthermore, stable Target 1 knockdown in a severe steatotic in vitro MASLD model presented alleviated inflammation and apoptosis but not steatosis, suggestive of Target 1’s function in anti-inflammatory and anti-apoptotic pathways that contribute to MASLD regression, especially in more adverse MASLD stages. Conclusion: Hereby, we have unveiled some of Target 1’s potential as a therapeutic target for liver regeneration which can possibly drive treatment for MASLD.