Identification of an immediate-early gene-activated fibroblast state in frozen shoulder capsular fibrosis.

Frozen shoulder (adhesive capsulitis) is characterized by progressive fibrotic remodeling of the shoulder joint capsule. To investigate the cellular programs underlying the fibrotic process, we integrate spatial transcriptomics, pseudotime inference, and in situ validation to comprehensively resolve fibroblast heterogeneity in human shoulder joint capsules. We identify three transcriptionally and spatially distinct fibroblast states: homeostatic, immediate-early gene (IEG)-activated, and pro-fibrotic. Notably, frozen shoulder exhibits a profound loss of homeostatic fibroblasts and a striking expansion of a FOS+JUN+EGR1+ IEG-activated fibroblast subset that is rare in normal capsules. Trajectory analysis positions these cells as a stress-responsive transitional state linking homeostasis to fibrosis. Spatial mapping and immunostaining confirm the widespread emergence of IEG-activated fibroblasts in diseased capsules. Together, our findings identify an IEG-activated fibroblast state associated with fibrotic remodeling in frozen shoulder and highlight fibroblast state plasticity as a key contributor to disease pathogenesis.