Tissues stiffen during aging and during the pathological progression of cancer, fibrosis, and cardiovascular disease. Extracellular matrix stiffness is emerging as a prominent mechanical cue that precedes disease and drives its progression by altering cellular behaviors. Targeting extracellular matrix mechanics, by preventing or reversing tissue stiffening or interrupting the cellular response, is a therapeutic approach with clinical potential. Major drivers of changes to the mechanical properties of the extracellular matrix include phenotypically converted myofibroblasts, transforming growth factor β (TGFβ), and matrix cross-linking. Potential pharmacological interventions to overcome extracellular matrix stiffening are emerging clinically. Aside from targeting stiffening directly, alternative approaches to mitigate the effects of increased matrix stiffness aim to identify and inhibit the downstream cellular response to matrix stiffness. Therapeutic interventions that target tissue stiffening are discussed in the context of their limitations, preclinical drug development efforts, and clinical trials.

在衰老过程中以及在癌症、纤维化和心血管疾病的病理进展过程中，组织会变硬。细胞外基质硬度正在成为一种显着的机械信号，它先于疾病并通过改变细胞行为来推动疾病的进展。通过预防或逆转组织硬化或中断细胞反应来靶向细胞外基质力学是一种具有临床潜力的治疗方法。细胞外基质机械特性变化的主要驱动因素包括表型转化的肌成纤维细胞、转化生长因子 β (TGFβ) 和基质交联。克服细胞外基质硬化的潜在药物干预措施正在临床上出现。除了直接瞄准硬化之外，减轻基质刚度增加的影响的替代方法旨在识别和抑制下游细胞对基质刚度的反应。针对组织硬化的治疗干预在其局限性、临床前药物开发工作和临床试验的背景下进行了讨论。