A chemically optimized, GalNAc-conjugated siRNA targeting HSD17B13 demonstrates efficacy in a human 3D organoid model of MASH, showcasing an alternative to animal testing.

Authors

Qin Meng, Xujia Wang, Yuxuan Zhang, Sudeep Pushpakom, Jun Yang, Hui Feng, Mu Wang

Published in

PloS one. Volume 21. Issue 8. Pages e0354751. Epub Aug 14, 2026.

Abstract

Animal models have limited ability to predict human metabolically dysfunction-associated steatohepatitis (MASH), creating a major obstacle in drug development. To address this challenge, we introduce an integrated drug discovery approach that combines rational small-interfering RNA (siRNA) design and chemical modifications to improve stability, validated in a complex human 3D NAC-organoid MASH model.
Using this system, we created new GalNAc-conjugated siRNAs targeting the 17β-hydroxysteroid dehydrogenase 13 (HSD17B13). The lead candidates were evaluated for stability in human serum and liver microsomes, off-target risks, and efficacy in the 3D organoid model that mimics key disease features such as steatosis and fibrosis.
Our main candidate, si-R5-42, demonstrated greater stability in human serum and liver microsomes, as well as fewer off-target risks. Most importantly, in the 3D organoid model, si-R5-42 successfully reduced disease markers. Its ability to lower hepatic steatosis and fibrogenesis was comparable to that of the clinical-phase candidate ARO-HSD.
This research provides a promising therapeutic candidate and a solid, human-relevant preclinical siRNA testing framework, reducing dependence on animal models.

PMID:
42599949
Bibliographic data and abstract were imported from PubMed on 15 Aug 2026.

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