SRS240 - IL-6/JAK/STAT3 signalling promotes ischaemia-reperfusion–induced renal allograft fibrosis

Abstract Background Renal allograft fibrosis, mainly marked by interstitial fibrosis and tubular atrophy (IF/TA), is a leading cause of late graft failure. Ischaemia–reperfusion injury (IRI) contributes significantly to fibrotic progression, yet underlying molecular mechanisms remain unclear. This study investigates the role of IL-6/JAK/STAT3 signalling in renal graft fibrosis using bulk-RNA sequences analyses and assesses the anti-fibrotic effect of the JAK1/2 inhibitor ruxolitinib. Methods Transcriptomic data were analysed from (1) five Gene Expression Omnibus datasets of renal allografts one year post-transplantation (Normal: n = 168; IF/TA: n = 113); and (2) human kidneys after 10 h of ex vivo machine perfusion (EVMP) (n = 9). Gene Ontology, KEGG, and GSEA were used for pathway enrichment. Genes related to IL-6/JAK/STAT3 and other fibrosis markers were selected for further statistical analysis. In vitro, human proximal tubular (TH1) cells were subjected to hypoxia–reoxygenation with or without ruxolitinib, and α-SMA expression were evaluated. Results Transcriptomic profiling revealed upregulation of the IL-6/JAK/STAT3 pathway during the transition from acute injury to chronic fibrosis. Notably, JAK1 was elevated after 10 h of EVMP, while JAK2 was predominantly upregulated in chronic graft fibrosis samples. Early and sustained activation of fibroblast markers and various pro-fibrotic genes was observed. In vitro, ruxolitinib significantly downregulated α-SMA expression in TH1 cells after reoxygenation. Conclusions IL-6/JAK/STAT3 signalling is an important mediator of IRI-induced renal graft fibrosis. JAK1/2 inhibition may offer a promising therapeutic approach to mitigate chronic graft deterioration.