Diabetic nephropathy (DN) is the most common cause of end-stage renal disease (ESRD). Currently, approximately 20-40% of individuals with diabetes are diagnosed with DN. Mesangial cells (MCs) are critical for maintaining and regulating glomerular filtration, and the abnormal proliferation of MCs causes the accumulation of mesangial extracellular matrix (ECM), further promoting glomerular dysfunction and renal diseases. Low molecular weight fucoidan (LMWF) extracted from Saccharina japonica could alleviate DN, but the mechanism was not analysed. Based on the ability of LMWF to ameliorate the human renal mesangial cell (HRMC) injury caused by advanced glycation end products (AGEs), we identified fibronectin (FN) as the most obviously impacted protein in the ECM-receptor interaction by proteomic analysis. The co-localization of LMWF and FN indicated direct interaction between them, and surface plasmon resonance (SPR) analysis confirmed the specific binding with a KD of 453.7?μmol?L-1. Positively charged protamine sulfate (PS) promoted the combination of LMWF and HRMCs and further enhanced the effect of LMWF on HRMC injury. Our results indicated that LMWF alleviates the HRMC injury caused by AGEs via binding FN and inhibiting the ECM-receptor interaction pathway. These results provide a foundation for the in-depth analysis of the mechanism of polysaccharide functions.,Copyright ? 2020. Published by Elsevier B.V.