2. Academic Validation
  3. Identification of NUV-244 as a PNPLA3 I148M degrading small molecule

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

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-173599
    PNPLA3 I148M Degrader