Donor-Resolved Analysis of HES1-Associated Fibroblast States in Systemic Sclerosis

Background/Objectives: We examined HES1-associated fibroblast states in systemic sclerosis (SSc) and the rationale for testing upstream γ-secretase inhibition with nirogacestat.

Methods

We analysed 325,636 skin cells from 230 donors across five non-redundant cohorts using complete computational transcription-factor screens, donor-level activity and trajectory analyses, multiome data and spatial assays. Donors or independent simulations were the inference units, with cohort adjustment and multiplicity correction where applicable. Three independent 200 ns molecular dynamics runs per condition compared nirogacestat-bound and ligand-deleted γ-secretase models.