Background The mechanism by which LMWH can delay the progression of diabetic nephropathy (DN) is not fully understood. Methods To further reveal the mechanism of LMWH treatment DN progression, we first verified the effect of LMWH in treatment DN through mouse models, and then quantified the kidney proteome by label-free, combined with bioinformation analysis to find key differentially expressed proteins. The mechanism by which LMWH causes differences in protein expression is revealed by cell experiments. Results Compared with the diabetic nephropathy group, the downstream proteins FABP1, Acaa1b, Acox2, Hmgcs2 and PLTP of the PPAR signaling pathway were significantly upregulated in the LMWH treatment group. The HS-binding protein FABP1 was used as the key protein to study the cellular mechanism, and it was found that the high glucose-high fat environment would degrade the HS of renal tubular epithelial cells, thereby reducing the endocytosis recruitment effect of renal tubules on FABP1. Conclusions LMWH can protect the HS of DN tubular epithelial cells from being destroyed, thereby ensuring the normal endocytosis of HS-mediated FABP1, reducing the loss of FABP1, and promoting the PPAR pathway to delay the progression of DN.