Njeim Rachel, Awada Bassel, Donow Haley, Gye Haley, Foster Cole, Kelly Colin, Molina Judith, Merscher Sandra, Giulianotti Marcello, Fornoni Alessia, Al-Ali Hassan
Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida 33136, United States.
Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida 33136, United States.
ACS Chem Biol. 2025 Jun 20;20(6):1406-1416. doi: 10.1021/acschembio.5c00212. Epub 2025 Jun 2.
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.
脂质稳态失调与包括神经、代谢、心血管、肿瘤和肾脏疾病在内的多种病理状况相关。我们之前表明，足细胞中脂滴（LD）的积累会导致糖尿病肾病（DKD）的进展，减少脂滴可保留足细胞功能并预防蛋白尿。在此，我们试图鉴定治疗病理性脂滴积累的化合物。我们利用人足细胞开发了一种表型分析方法，并将其用于筛选包含超过4500万个独特小分子的组合文库。这导致鉴定出一系列能有效减少应激足细胞中脂滴积累的化合物。机制研究表明，这些化合物激活脂质自噬，减少脂滴积累，并使足细胞免于细胞死亡。相比之下，已知诱导一般自噬的化合物未能模拟这些作用，表明存在一种新的脂质自噬特异性作用机制（MoA），这通过无偏表型分析得到了证实。这种治疗策略的一个优点是它不仅有可能阻止病理性脂质积累的进展，还能使其逆转。这些化合物将作为揭示治疗DKD和其他具有相似病因疾病的新型药物靶点和治疗MoA的工具。
