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
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
