bims-raghud 2026-05-03 papers

Issue of 2026–05–03
two papers selected by
Irene Sambri, TIGEM

Stem Cell Res Ther. 2026 Apr 26. pii: 167. [Epub ahead of print]17(1):

Induction of fibrosis in human kidney organoids delineates mechanisms and therapeutic targets of fibrotic kidney disease.

Markus C Doeser, Julia Raimann, Maren Beuke, Zeynep Kilcan, Amélie F Menke, Barbara M Klinkhammer, Peter Boor, Hans R Schöler, Hermann Pavenstädt.

BACKGROUND: Developing regenerative therapies to restore kidney function in patients with progressive renal disease represents a major challenge for modern molecular nephrology. Kidney organoids, three-dimensional kidney-like structures, which can now be generated by the directed differentiation of human pluripotent stem cells, have emerged as a powerful tool to study kidney development, physiology, and mechanisms of renal disease in vitro. Ultimately, kidney organoids may serve as an experimental platform to unravel the pathomechanisms of renal fibrosis and to test regenerative treatment approaches targeting fibrotic kidney diseases. However, the fibrotic phenotype in kidney organoids and its utility as a disease model remain to be fully characterized.
METHODS: Three-dimensional self-organizing kidney organoids containing nephrons and stromal cells were exposed to TGF-β1 cytokine to induce fibrotic remodeling. Organoids were analyzed by RNA sequencing and histology.
RESULTS: Activation of TGF-β1 signaling in kidney organoids induced hallmarks of human kidney fibrosis, such as tubular atrophy, glomerulosclerosis, and interstitial fibrosis. RNA sequencing highlighted differential regulation of key pathways in kidney fibrosis: epithelial-to-mesenchymal transition, inflammation, metabolism, and JAK/STAT signaling. We identified candidate mediators of kidney fibrosis such as the JAK-STAT downstream target PIM1. Inhibition of PIM1 with the small molecule AZD1208 attenuated fibrosis development in the organoids.
CONCLUSIONS: Kidney organoids are an amenable system for modeling kidney fibrosis and may guide therapeutic discovery.

Keywords: 3D cell culture; Chronic kidney disease; Disease modeling; Glomerulosclerosis; Human pluripotent stem cells; JAK/STAT; Renal failure

DOI: https://doi.org/10.1186/s13287-026-05030-4

Br J Pharmacol. 2026 Apr 26.

Curcumin controls lysosomal acidification and exocytosis to ameliorate lysosomal cholesterol accumulation in Niemann-Pick type C disease.

Hongyu Chen, Mengli Zhao, Yu Luo, Xiaohe Chu, Dan Li.

BACKGROUND AND PURPOSE: Niemann-Pick type C disease (NPCD) is a rare and fatal lysosomal storage disorder. There are limited therapies for NPCD, although multiple small-molecule compounds have shown therapeutic potential for NPCD. Curcumin (CUR), a polyphenolic compound enriched in turmeric, has cholesterol-lowering effects via regulating intestinal cholesterol absorption and liver cholesterol synthesis. CUR normalises sphingolipid trafficking and stimulates exosome/microvesicle release, increases cytosolic Ca2+ levels, and enhances lysosomal activation via mTOR suppression and TFEB activation. How CUR specifically targets lysosomal cholesterol has not been fully clarified.
EXPERIMENTAL APPROACH: Effects of curcumin on lysosomal cholesterol accumulation were evaluated in NPC1 cell models. Filipin staining, immunofluorescence, surface LAMP1 and NAGase activity and Cathepsin B activity were investigated to evaluate lysosomal cholesterol, TFEB translocation, lysosomal exocytosis and hydrolytic activity. Lysosomal acidification was determined by Lysotracker Red, Oregon Green, and sfGFP/mCherry transfection. CRISPR/Cas9 and siRNA interference were used to investigate the role of TFEB/TFE3 and TRPML1 in curcumin-induced cholesterol reduction.
KEY RESULTS: CUR alleviates lysosomal cholesterol accumulation in NPC1 cells in a TFEB- and TFE3-dependent manner. CUR enhanced lysosomal acidity and promoted calcium-dependent lysosomal exocytosis, which contributed to CUR-mediated lysosomal cholesterol clearance. The combination of CUR with specific agonists (ML-SAs) of MCOLN1/TRPML1, a lysosomal cation channel required for lysosomal exocytosis, improved lysosomal cholesterol clearance.
CONCLUSION AND IMPLICATIONS: CUR reduces lysosomal cholesterol accumulation in NPC1 cells by activating TFEB/TFE3 pathways and promoting Ca2+- and TRPML1-dependent lysosomal exocytosis. These findings support curcumin and its analogues as potential therapeutics for NPCD and other diseases of lysosomal storage.

Keywords: NPC1; cholesterol; curcumin; lysosomal acidification; lysosome exocytosis

DOI: https://doi.org/10.1111/bph.70448