TRPV4 is a non-selective cation channel with ~5-10 fold greater calcium permeability than sodium 1 that functions as a mechanosensitive polymodal ion channel expressed broadly across tissues 2. Functionally, TRPV4 responds to diverse physical stimuli including cell swelling, mechanical stretch, and heat, as well as chemical stimuli including endocannabinoids and arachidonic acid metabolites 1. TRPV4 operates as a homotetrameric complex, forming calcium-permeable channels that regulate intracellular calcium homeostasis 13. Mechanistically, TRPV4 mediates crystal-induced inflammation by activating NLRP3 inflammasome in synovial macrophages and human PBMCs, driving interleukin-1β production in response to monosodium urate crystals 4. During sepsis, TRPV4 regulates macrophage glucose uptake via GLUT1 and phagolysosome maturation, limiting lung injury through enhanced bacterial clearance 5. In endothelial cells, TRPV4 mediates localized calcium entry at caveolin-1-rich microdomains, activating nitric oxide synthase to suppress inflammatory gene expression 6. Genetically, TRPV4 mutations cause multiple channelopathies including Charcot-Marie-Tooth disease type 2C, spinal muscular atrophy, and brachyolmia 7. Therapeutically, TRPV4 antagonism shows potential for treating edema, pain, gastrointestinal disorders, and lung diseases 2, with first-in-human trials initiated in heart failure patients.