Role of DZ2002 in reducing corneal graft rejection in rats by influencing Th17 activation via inhibition of the PI3K/AKT pathway and downregulation of TRAF1.

To investigate the mechanism of DZ2002, a reversible type III S-adenosyl-l-homocysteine hydrolase (SAHH) inhibitor, in alleviating corneal graft rejection in rats through the downregulation of TRAF1 and modulation of Th17 differentiation, so as to provide a new therapeutic strategy for corneal graft rejection. Rat models of corneal graft rejection were constructed and treated with DZ2002 eye drops. Metabolomics and transcriptomics sequencing analyses were used to identify the key metabolite, homocysteine, and its associated gene, TRAF1. Histological assessments were conducted to evaluate the effect of DZ2002 on corneal graft rejection. Additionally, the underlying mechanism of action was explored through Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Homocysteine emerged as a key metabolite involved in corneal graft rejection, and DZ2002 could significantly decrease the rejection index and reduce the opacity and edema of corneal grafts. The effect of DZ2002 in alleviating rejection was attributed to the downregulation of TRAF1 expression, inhibition of the PI3K/AKT pathway, decreased expression of chemokine CCL5 in the aqueous humor, and suppression of the differentiation of T cells into Th17 cells. DZ2002 was effective in reducing corneal graft rejection in rats by downregulating TRAF1 and modulating Th17 differentiation.