Extracellular Matrix Components and Mechanosensing Pathways in Health and Disease. Aikaterini Berdiaki, Monica Neagu, Petros Tzanakakis, Ioanna Spyridaki, Serge Pérez, Dragana Nikitovic. Abstract: Glycosaminoglycans (GAGs) and proteoglycans (PGs) are essential components of the extracellular matrix (ECM) with pivotal roles in cellular mechanosensing pathways. GAGs, such as heparan sulfate (HS) and chondroitin sulfate (CS), interact with various cell surface receptors, including integrins and receptor tyrosine kinases, to modulate cellular responses to mechanical stimuli. PGs, comprising a core protein with covalently attached GAG chains, serve as dynamic regulators of tissue mechanics and cell behavior, thereby playing a crucial role in maintaining tissue homeostasis. Dysregulation of GAG/PG-mediated mechanosensing pathways is implicated in numerous pathological conditions, including cancer and inflammation. Understanding the intricate mechanisms by which GAGs and PGs modulate cellular responses to mechanical forces holds promise for developing novel therapeutic strategies targeting mechanotransduction pathways in disease. This comprehensive overview underscores the importance of GAGs and PGs as key mediators of mechanosensing in maintaining tissue homeostasis and their potential as therapeutic targets for mitigating mechano-driven pathologies, focusing on cancer and inflammation. Keywords: mechanotransduction; proteoglycans; glycosaminoglycans; mechanosensing; cancer; inflammation; syndecans; glypican. The review discusses the role of PGs and GAGs, critical components of the ECM, in mechanotransduction. It covers the mechanical properties of the ECM, the interplay between the ECM and its specific component, the cellular glycocalyx (GCX), and the roles of various ECM components such as collagens, elastin, PGs, GAGs, glycoproteins, and cross-linking molecules. The review also explores the mechanisms of mechanosensing, including the roles of integrins, cadherins, PIEZO, TRP, and GPCR receptors in transmitting mechanical cues. The review highlights the importance of GAGs and PGs in modulating cell mechanotransduction through various pathways, including their interactions with integrins and cadherins, and their roles in ECM remodeling and plasticity. The review emphasizes the significance of understanding these mechanisms for developing therapeutic strategies targeting mechanotransduction pathways in disease.Extracellular Matrix Components and Mechanosensing Pathways in Health and Disease. Aikaterini Berdiaki, Monica Neagu, Petros Tzanakakis, Ioanna Spyridaki, Serge Pérez, Dragana Nikitovic. Abstract: Glycosaminoglycans (GAGs) and proteoglycans (PGs) are essential components of the extracellular matrix (ECM) with pivotal roles in cellular mechanosensing pathways. GAGs, such as heparan sulfate (HS) and chondroitin sulfate (CS), interact with various cell surface receptors, including integrins and receptor tyrosine kinases, to modulate cellular responses to mechanical stimuli. PGs, comprising a core protein with covalently attached GAG chains, serve as dynamic regulators of tissue mechanics and cell behavior, thereby playing a crucial role in maintaining tissue homeostasis. Dysregulation of GAG/PG-mediated mechanosensing pathways is implicated in numerous pathological conditions, including cancer and inflammation. Understanding the intricate mechanisms by which GAGs and PGs modulate cellular responses to mechanical forces holds promise for developing novel therapeutic strategies targeting mechanotransduction pathways in disease. This comprehensive overview underscores the importance of GAGs and PGs as key mediators of mechanosensing in maintaining tissue homeostasis and their potential as therapeutic targets for mitigating mechano-driven pathologies, focusing on cancer and inflammation. Keywords: mechanotransduction; proteoglycans; glycosaminoglycans; mechanosensing; cancer; inflammation; syndecans; glypican. The review discusses the role of PGs and GAGs, critical components of the ECM, in mechanotransduction. It covers the mechanical properties of the ECM, the interplay between the ECM and its specific component, the cellular glycocalyx (GCX), and the roles of various ECM components such as collagens, elastin, PGs, GAGs, glycoproteins, and cross-linking molecules. The review also explores the mechanisms of mechanosensing, including the roles of integrins, cadherins, PIEZO, TRP, and GPCR receptors in transmitting mechanical cues. The review highlights the importance of GAGs and PGs in modulating cell mechanotransduction through various pathways, including their interactions with integrins and cadherins, and their roles in ECM remodeling and plasticity. The review emphasizes the significance of understanding these mechanisms for developing therapeutic strategies targeting mechanotransduction pathways in disease.