Mesoscale tissue states in fibrosis: from pathway targeting to state-directed therapy

Fibrosis is a major cause of organ dysfunction, yet current antifibrotic therapies slow functional decline without durably arresting disease progression or restoring tissue architecture. This therapeutic ceiling suggests that determinants of progressive fibrosis extend beyond individual molecular pathways. In this review, we propose that progressive fibrosis represents a pathological state transition in which a plastic tissue microenvironment becomes a self-sustaining mesoscale fibrotic tissue module. Within this state, cellular plasticity is retained but misdirected towards maladaptive repair. Tissue behaviour emerges from spatial organisation and coupled multicellular dynamics that cannot be predicted from individual signalling pathways alone. This framework explains why pathway-centric therapies attenuate fibrogenic activity without reversing the underlying tissue state. We propose a state-directed paradigm in which pathological tissue modules must be unlocked to restore tissue plasticity and re-establish tissue homoeostasis.