*Purpose: Liver ischemia-reperfusion injury, an innate-immune dominated hepatocellular damage, is a risk factor of early graft dysfunction and rejection in liver transplantation (LT). HuR, an ubiquitously expressed member of the Hu protein family, selectively binds and stabilizes ARE-containing mRNAs encoding for protooncogenes/cytokines. Previous studies indicate its anti-inflammatory functions in animal models while its contribution in LT remains unknown. A recent in vitro study found that HuR not only stabilizes mRNA but may also enhance translation for heme oxygenase 1 (HO-1), an established anti-inflammatory/cytoprotective molecule. However, HuR/HO-1 communication in clinical LT remains unknown. By analyzing human LT biopsies (Bx), we investigated the impact of graft HuR expression on clinical outcomes and crosstalk with HO-1.

*Methods: Hepatic Bx were obtained at 2 hours after reperfusion from human LT recipients (n=51) recruited under IRB protocol. Bx were retrospectively analyzed by RT-PCR (CD80/CD86/Cathepsin G/CD4/CD28/HO-1) and WB (HuR/HO-1), while human LT recipients were split evenly into low-HuR (n=26) and high-HuR (n=25) expression groups.

*Results: In 51 LT Bx, HuR expression negatively correlated with sALT levels (r=-0.3139, p=0.0249) at POD1. HuR levels also negatively correlated with mRNA coding for CD80 (r=-0.3555, p=0.0153), CD86 (r=-0.3117, p=0.0349), macrophage markers; Cathepsin G (r=-0.3907, p=0.0073), a neutrophil marker; CD4 (r=-0.2957, p=0.0460), CD28 (r=-0.2559, p=0.0861), T-cell markers. Compared with low-HuR expression group (n=26), high-HuR cases (n=25) were characterized by: 1/ decreased levels of sALT (266.3±37.7 vs 449.4±62.7 IU/L, p=0.0356) at POD1; 2/ suppressed mRNA expression coding for CD80 (0.84±0.07 vs 1.00±0.08), CD86 (0.87±0.05 vs 1.00±0.07), Cathepsin G (0.82±0.06 vs 1.00±0.08), CD4 (0.72±0.07 vs 1.00±0.13), CD28 (0.83±0.07 vs 1.00±0.09); 3/ experienced lower incidence of early allograft dysfunction (4.0% vs 11.5%); as well as 4/ shorter post-LT hospital stay (35.8±4.3 vs 45.5±8.2 days) and improved post-LT graft survival (2-years: 97.0 vs 80.7%, p=0.0543). HO-1 expression positively correlated with HuR protein levels (r=0.4018, p=0.0035), whereas correlation between HO-1 mRNA and HO-1 protein was relatively weak (r=0.1191, p=0.4305), implying promotion of HO-1 mRNA translation by HuR dictated protein HO-1 levels.

*Conclusions: This translational study in LT patients documents the association between high HuR expression levels and reduced inflammatory gene expression pattern, enhanced HO-1 protein levels and favorable recipient outcomes. Our data imply HuR plays an important and previously unrecognized role in the regulation of innate/adaptive inflammatory hepatic damage in clinical LT as well as the possibility that HO-1 upregulation might be a part of its cytoprotective phenotype.

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