Pharmacological inhibition of small extracellular vesicle secretion by ALK5i SD‐208 via lysosomal rerouting of CD63+ compartments

Sanwlani, Rahul, Thompson, Georgina H., Bramich, Kyle, Ang, Ching‐Seng, Trowbridge, Millie L., Duringer, Chris E., Stolojan, Vlad, Davidson, Sean M., Savvatis, Konstantinos, McVey, John H., Mathivanan, Suresh, Clayton, Aled ORCID: https://orcid.org/0000-0002-3087-9226 and Camelliti, Patrizia 2026. Pharmacological inhibition of small extracellular vesicle secretion by ALK5i SD‐208 via lysosomal rerouting of CD63+ compartments. Journal of Extracellular Vesicles 15 (9) , e70362. 10.1002/jev2.70362

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Abstract

Pharmacological tools to selectively modulate extracellular vesicle (EV) secretion are scarce. Here, we identify the ALK5 (TGF-β receptor I) inhibitor SD-208 as a potent suppressor of small EV (sEV) secretion that acts independently of its canonical anti-fibrotic activity. SD-208 not only reversed myofibroblast activation but also markedly inhibited sEV secretion. Strikingly, this inhibitory effect persisted in non-activated cardiac fibroblasts and non-fibrotic HEK293 cells, demonstrating that SD-208 regulates EV secretion through mechanisms uncoupled from TGF-β/Smad signalling. Mechanistic analyses revealed that SD-208 disrupts vesicle trafficking rather than EV biogenesis. Reduced secretion of CD63+ EVs was accompanied by intracellular accumulation of CD63+ structures and their selective diversion into LAMP1+ lysosomes. Proteomic profiling of SD-208-treated and control HEK293 cells and cardiac fibroblasts revealed dysregulation of vesicle trafficking pathways, enrichment of ubiquitin ligase complexes, and enhanced endosome-to-lysosome transport. Together, these findings demonstrate that SD-208 diverts CD63+ multivesicular bodies (MVBs) from a secretory fate toward lysosomal degradation. This work identifies SD-208 as a small-molecule tool to interrogate the secretory-versus-degradative fate of MVBs and uncovers a new regulatory link between lysosomal pathways and EV trafficking. Beyond its established role as an anti-fibrotic agent, SD-208 provides mechanistic and therapeutic opportunities for the control of EV secretion in diseases such as fibrosis, cardiac remodelling, hypertrophic cardiomyopathy, and cancer.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine
Publisher:	Wiley
ISSN:	2001-3078
Date of First Compliant Deposit:	1 September 2026
Date of Acceptance:	4 August 2026
Last Modified:	01 Sep 2026 11:15
URI:	https://orca.cardiff.ac.uk/id/eprint/189287

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