TNFAIP6 is a critical regulator of extracellular matrix organization and inflammatory responses with diverse pathophysiological roles. Mechanistically, TNFAIP6 catalyzes heavy chain transfer from inter-alpha-inhibitor complexes to hyaluronan, organizing pericellular matrices that modulate cell signaling and leukocyte recruitment 12. The protein assembles hyaluronan-rich matrices essential for oocyte fertilization through cumulus cell expansion 3. TNFAIP6 regulates immune cell trafficking by altering hyaluronan-CD44 interactions on vascular endothelium and modulates chemokine gradients, potentially limiting excessive neutrophil recruitment 45. In bone metabolism, TNFAIP6 inhibits BMP2-dependent osteoblast differentiation and protects against inflammation-induced bone erosion by blocking RANKL-dependent osteoclast activation 67. Clinically, TNFAIP6 emerges as a biomarker in multiple pathologies. In diabetic foot ulcers, healing-associated fibroblasts show elevated TNFAIP6 expression 8. TNFAIP6 serves as a diagnostic biomarker for intervertebral disc degeneration 9 and osteoarthritis with type 2 diabetes, where upregulation correlates with pro-inflammatory CD14+ monocyte recruitment 10. In glioblastoma, TNFAIP6 secretion by cancer stem cells promotes tumor growth via EGFR-PI3K-AKT signaling while inducing suppressive macrophage phenotypes 11. In ovarian cancer, N-glycosylation-stabilized TNFAIP6 drives metastasis through PI3K-AKT pathway activation and immune-suppressive microenvironment establishment 12. TNFAIP6 shows diagnostic potential in chr2 kidney disease hemodialysis patients 13.