The gene regulatory networks shaping macrophage plasticity and altered function in fibrosis

Tissue inflammation and its resolution are fundamental physiological processes that ensure homeostasis and tissue integrity following injury. A precise balance between pro-inflammatory and pro-resolving mechanisms promotes proper tissue repair, whereas dysregulation of these pathways results in chronic damage and fibrosis. This complex multicellular phenomenon ultimately manifests in extensive extracellular matrix (ECM) deposition and organ failure. Although the core transcriptional programs are highly conserved throughout evolution and across different species and tissues, distinct features arise under the influence of specific tissue microenvironments. The functionally divergent phenotypes and widespread heterogeneity of macrophages enable them to play a key modulatory role along the inflammation-resolution-fibrosis axis. Recent advances in epigenetic and transcriptomic profiling have revealed novel regulatory circuits and candidate transcriptional regulators governing macrophage phenotypes in fibrotic contexts. In this review, we aim to integrate current knowledge on the complex, context-dependent regulatory mechanisms and dysfunction of macrophages in fibrosis. We highlight the importance of macrophage ontogeny, signal- and metabolism-dependent transcriptional regulation, and chromatin remodeling in disease progression, with particular attention to therapeutic perspectives.