Identification of NUV-244 as a PNPLA3 I148M degrading small molecule

  • iScience. 2025 Apr 8;28(5):112384. doi: 10.1016/j.isci.2025.112384.
Patrick Steigemann  1 ,  Nico Braeuer  1 ,  Vera Puetter  1 ,  Nina Zablowsky  1 ,  Katrin Juenemann  1 ,  Franz von Nussbaum  1 ,  Ralf Lesche  1 ,  Nicole Dittmar  1 ,  David Schaller  1 ,  Zuzanna Makowska  1 ,  Filippos Klironomos  1 ,  Susanne Schwarz  1 ,  Daniela Launhardt  1 ,  Benjamin Bader  1 ,  Martin Lange  1 ,  Holger Steuber  1 ,  Mary Helen Black  2 ,  Jonathan S Packer  2 ,  Stefano Romeo  3 ,  Stephan Fasler  2 ,  Lisa Bedford  2 ,  Frederick E Dewey  2
Affiliations
  • 1. Nuvisan ICB GmbH, Müllerstrasse 178, 13353 Berlin, Germany.
  • 2. Foresite Labs, San Francisco, CA, USA.
  • 3. University of Gothenburg, Gothenburg, Sweden.
PMID: 40322074 DOI: 10.1016/j.isci.2025.112384
Abstract

The PNPLA3 I148M variant is a key genetic determinant of metabolic dysfunction-associated steatotic Liver Disease (MASLD) and related conditions, contributing to Lipid Metabolism dysregulation and disease progression. To identify small molecules that modulate PNPLA3 I148M, we conducted a high-content screen of over 820,000 compounds and identified NUV-244, a potent degrader of PNPLA3 I148M in liver-derived cells. NUV-244 reduces PNPLA3 I148M levels on lipid droplets via the ubiquitin-proteasome system, involving the E3 Ligase BFAR, without affecting PNPLA2. It restores lipid droplet morphology and improves cellular fitness in PNPLA3 I148M-expressing cells. These findings provide a tool to investigate PNPLA3 I148M function and offer a potential strategy for developing targeted therapies for MASLD and related diseases. By enabling selective degradation of PNPLA3 I148M, this approach expands therapeutic possibilities beyond genetic manipulation, addressing a critical need in metabolic liver Disease Research.

Keywords
Biochemistry; Biological sciences; Cell biology; Functional aspects of cell biology.
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