Article
Nonalcoholic steatohepatitis (NASH) is the most common chronic liver disease globally and a leading cause for liver transplantation in the US. Its pathogenesis remains imprecisely defined. We combined two high-resolution modalities to tissue samples from NASH clinical trials, machine learning (ML)-based quantification of histological features and transcriptomics, to identify genes that are associated with disease progression and clinical events. A histopathology-driven 5-gene expression signature predicted disease progression and clinical events in patients with NASH with F3 (pre-cirrhotic) and F4 (cirrhotic) fibrosis. Notably, the Notch signaling pathway and genes implicated in liver-related diseases were enriched in this expression signature. In a validation cohort where pharmacologic intervention improved disease histology, multiple Notch signaling components were suppressed. Jake Conway, 1,4 Maryam Pouryahya, 1,4 Yevgeniy Gindin, 2 David Z. Pan, 2 Oscar M. Carrasco-Zevallos, 1 Victoria Mountain, 1 G. Mani Subramanian, 3 Michael C. Montalto, 1 Murray Resnick, 1 Andrew H. Beck, 1 Ryan S. Huss, 3 Robert P. Myers, 3 Amaro Taylor-Weiner, 1 Ilan Wapinski, 1,5,* and Chuhan Chung 2,*1PathAI, Boston, MA, USA
2Gilead Sciences, Inc., Foster City, CA, USA
3OrsoBio, Palo Alto, CA, USA
4These authors contributed equally
5Lead contact
*Correspondence: ilan.wapinski@pathai.com (I.W.), chuhanchung@inipharm.com (C.C.)
https://doi.org/10.1016/j.xcrm.2023.101016
