The extracellular matrix: structure, composition, biological functions, diseases, and therapeutic targets

The extracellular matrix (ECM) is a highly organised and dynamic regulator of tissue structural integrity and biochemical signalling, and its dysregulation is a hallmark of fibrosis and cancer. Recent evidence highlights the critical role of epigenetic mechanisms in controlling ECM-related gene expression and remodelling activity. This review integrates recent advances in understanding how epigenetic mechanisms govern ECM composition, remodelling, and mechanotransduction, and how reciprocal ECM-derived signals reshape the epigenetic landscape. Growing evidence links DNA methylation, histone modifications, and non-coding RNAs to the regulation of key ECM components, matrix-modifying enzymes, and stiffness-associated signalling pathways, including TGF-β, Wnt, and PI3K/Akt are summarised in this review. The bidirectional feedback between altered ECM mechanics and epigenetic enzyme activity is emphasised, showing how matrix stiffening and aberrant epigenetic programming cooperatively drive pathological tissue remodelling and tumour progression. This review summarises findings from in vitro systems, animal models, and human disease studies that illustrate the functional consequences of ECM-epigenetic crosstalk. The emerging therapeutic approaches targeting the ECM-epigenetic axis, including epigenetic modulators and ECM-directed interventions, outline current challenges and future directions for restoring matrix homeostasis in disease. Together, this review provides an integrated framework for understanding the bidirectional ECM-epigenetic interactions and their translational relevance in molecular biomedicine.