**Background:** Cellular mechanotransduction is the conversion of mechanical signals into biochemical signals that regulate cell activities and metabolism. Mechanical cues such as hydrostatic pressure (HP), fluid shear stress (FSS), tensile force (TF), extracellular matrix (ECM) stiffness, and extracellular fluid (ECF) viscosity are critical for embryonic development, tissue repair, and regeneration. However, prolonged excessive mechanical stimulation can lead to pathological processes including multi-organ fibrosis, tumorigenesis, and cancer immunotherapy resistance. This review aims to comprehensively summarize the characteristics, regulatory mechanisms, key effectors, signaling pathways, and therapeutic targets of mechanical cues in health and disease.
**Methods:** The authors conducted a narrative review of the literature, systematically summarizing the characteristics and molecular mechanisms of typical mechanical cues (HP, FSS, TF, ECM stiffness, ECF viscosity) in normal conditions and diseases. They listed key mechanosensitive effectors (Piezo channels, integrins, YAP/TAZ, TRPV4) and reviewed key signaling pathways (RhoA/ROCK, TGFβ/Smad, JAK/STAT, Wnt/β-catenin, ERK1/2) and clinical applications targeting mechanical cue-related diseases. The review includes data from clinical trials (e.g., targeting integrins, YAP/TAZ) and discusses fibrosis in multiple organs (lung, liver, kidney, heart) and cancer cell behavior.
**Key Results:** The review details the roles of mechanical cues in various tissues. For example, HP in the interstitial cavity is approximately −4 cmH2O, in solid tumors 25–40 cmH2O, and in liver fibrosis >5 mmHg. FSS in large blood vessels is ~10 dyn/cm² and in arterioles ~50 dyn/cm². ECM stiffness in normal lung is ~1 kPa, increasing to 30–50 kPa in idiopathic pulmonary fibrosis (IPF); normal liver stiffness is 1.5–4.5 kPa, rising to 4.1–12.9 kPa (early fibrosis) and 16.3–48 kPa (late fibrosis). Key effectors include Piezo1/2 (sensing shear stress, stretch, HP), integrins (24 heterodimeric pairs), and YAP/TAZ (transcriptional coactivators). Signaling pathways such as RhoA/ROCK, TGFβ/Smad, JAK/STAT, Wnt/β-catenin, and ERK1/2 are activated by mechanical cues. The review also highlights clinical trials targeting integrins (e.g., volociximab, vedolizumab, IDL-2965, PLN-74809) and YAP/TAZ (e.g., simvastatin, ION537, zoledronate, IK-930). In fibrosis, mechanical cues activate fibroblasts, myofibroblasts, and immune cells, leading to ECM deposition. In cancer, ECM stiffness (5–10 times higher than normal tissue) promotes tumor growth, invasion, metastasis, and immunotherapy resistance via PD-L1 upregulation and immune cell modulation.
**Clinical Implications:** Understanding cellular mechanotransduction provides insights into therapeutic targets for fibrotic diseases (pulmonary, liver, renal, cardiac fibrosis), cancer, and other conditions. Targeting mechanosensitive effectors (e.g., Piezo1 inhibitors, integrin antagonists, YAP/TAZ inhibitors) and signaling pathways (e.g., TGFβ, RhoA/ROCK) may offer novel treatments. Clinical trials are ongoing for integrin-targeted therapies (e.g., vedolizumab for inflammatory bowel disease, PLN-74809 for IPF) and YAP/TAZ inhibitors (e.g., IK-930 for solid tumors). The review also suggests that adeno-associated virus (AAV)-mediated gene therapy and 3D culture systems may advance future research and therapies.