2. Academic Validation
  3. Novel Lipophagy Inducers as Potential Therapeutics for Lipid Metabolism Disorders

Novel Lipophagy Inducers as Potential Therapeutics for Lipid Metabolism Disorders

  • ACS Chem Biol. 2025 Jun 20;20(6):1406-1416. doi: 10.1021/acschembio.5c00212.
Rachel Njeim 1 2,  Bassel Awada 3,  Haley Donow 4,  Haley Gye 1 2,  Cole Foster 3,  Colin Kelly 3,  Judith Molina 1 2,  Sandra Merscher 1 2,  Marcello Giulianotti 5,  Alessia Fornoni 1 2 6,  Hassan Al-Ali 1 2 3 6 7 8
Affiliations

Affiliations

  • 1 Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida 33136, United States.
  • 2 Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida 33136, United States.
  • 3 The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, Florida 33136, United States.
  • 4 Center for Translational Science, Florida International University, Port St. Lucie, Florida 34987, United States.
  • 5 Department of Medicinal Chemistry & Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455, United States.
  • 6 Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida 33136, United States.
  • 7 Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, Florida 33136, United States.
  • 8 Frost Institute for Data Science and Computing, University of Miami Miller School of Medicine, Miami, Florida 33136, United States.
PMID: 40456060 DOI: 10.1021/acschembio.5c00212
Abstract

Dysregulation of lipid homeostasis is associated with a wide range of pathologies encompassing neurological, metabolic, cardiovascular, oncological, and renal disorders. We previously showed that lipid droplet (LD) accumulation in podocytes contributes to the progression of diabetic kidney disease (DKD) and reducing LDs preserves podocyte function and prevents albuminuria. Here, we sought to identify compounds that treat pathological LD accumulation. We developed a phenotypic assay using human podocytes and deployed it to screen a combinatorial library comprising over 45 million unique small molecules. This led to the identification of a compound series that effectively reduces LD accumulation in stressed podocytes. Mechanistic studies revealed that these compounds activate lipophagy, reduce LD accumulation, and rescue podocytes from cell death. In contrast, compounds known to induce general Autophagy failed to mimic these effects, indicating a novel lipophagy-specific mechanism of action (MoA), which was confirmed by unbiased phenotypic profiling. An advantage of this therapeutic strategy is its potential to not only halt the progression of pathological lipid accumulation but also reverse it. These compounds will serve as tools for uncovering novel drug targets and therapeutic MoAs for treating DKD and Other Diseases with similar etiologies.

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