Novel Lipophagy Inducers as Potential Therapeutics for Lipid Metabolism Disorders

Njeim, R.; Awada, B.; Donow, H.; Gye, H.; Foster, C.; Kelly, C.; Molina, J.; Merscher, S.; Giulianotti, M.; Fornoni, A.; Al-Ali, H.

doi:10.1101/2025.03.11.642628

bioRxiv · 10.1101/2025.03.11.642628

Novel Lipophagy Inducers as Potential Therapeutics for Lipid Metabolism Disorders

Njeim, R.·Awada, B.·Donow, H.·Gye, H.·Foster, C.·Kelly, C.·Molina, J.·Merscher, S.·Giulianotti, M.·Fornoni, A.·Al-Ali, H.

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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 reduce 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 with 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. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=39 SRC="FIGDIR/small/642628v1_ufig1.gif" ALT="Figure 1"> View larger version (12K): org.highwire.dtl.DTLVardef@16039e2org.highwire.dtl.DTLVardef@7865c3org.highwire.dtl.DTLVardef@60e886org.highwire.dtl.DTLVardef@41db90_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Njeim, R., Awada, B., Donow, H., Gye, H., Foster, C., Kelly, C., Molina, J., Merscher, S., Giulianotti, M., Fornoni, A., Al-Ali, H.. 2025-03-13. Novel Lipophagy Inducers as Potential Therapeutics for Lipid Metabolism Disorders. https://doi.org/10.1101/2025.03.11.642628

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