Fibroblast mechanopharmacology: mechanical regulation of fibroblast states and therapeutic response

Fibroblasts integrate mechanical and biochemical signals to maintain tissue integrity, yet sustained mechanical remodeling drives pathological phenotypes and modifies therapeutic responses. Matrix stiffness, collagen structure, tissue loading and fluid forces activate coordinated mechanosensory systems that regulate cytoskeletal, transcriptional, nuclear and metabolic programs. These pathways control overlapping repair, inflammatory, contractile and senescent fibroblast states, whose persistence and reversibility depend on tissue context and mechanical history. This review introduces fibroblast mechanopharmacology as a framework connecting the mechanical microenvironment, fibroblast plasticity and drug responses in fibrosis, cancer, cardiovascular remodeling and chronic inflammation. We discuss how fibroblast–matrix feedback affects drug delivery, signaling reliance, stable cellular functions and immune infiltration, shaping treatment efficacy independently of target expression. Such mechanisms support combined strategies including matrix normalization, mechanotransduction blockade, antifibrotic therapy, cell-state reprogramming and stromal–immune co-targeting. We also address how mechanically tuned cultures and human tissue models separate poor drug exposure from changed cellular sensitivity, and distinguish blocking fibroblast activation from reversing established dysfunction. Combining mechanical readouts, fibroblast-state profiling and functional drug testing can tailor interventions to disease-driving mechanical conditions and cellular dependencies. This perspective advances therapies designed around mechanical context and state reversibility without disrupting normal tissue repair.