Liver fibrosis is a leading cause of morbidity and mortality worldwide. Whereas acute injury or infection can trigger a self-resolving inflammatory response, chronic tissue injury triggers persistent inflammation-induced fibrosis. In Science Translational Medicine, Moreno-Lanceta et al. examine the role of the E3 ubiquitin ligase RNF41 in the progression of hepatic fibrosis, and how altered RNF41 expression contributes to the resolution of fibrotic tissue damage. RNF41 has been reported to dampen inflammatory responses and promote tissue repair. In the present study, liver-resident CD11b+ macrophages from individuals with liver cirrhosis had reduced RNF41 expression compared with healthy controls. A similar reduction in Rnf41 expression was seen in several mouse models of liver fibrosis. Stimulation with the inflammatory cytokine TNF initially increased RNF41 expression in macrophages, but prolonged exposure to TNF decreased RNF41 expression. The authors designed a graphene nanoparticle-based gene delivery system to modulate Rnf41 expression in mouse liver macrophages in vivo. Delivery of Rnf41 led to a decrease in fibrotic lesions and a loss of collagen deposition. This response also increased the expression of IGF1 and thereby enhanced hepatocyte proliferation, which suggests that enhancing RNF41 expression promotes the repair of fibrotic tissues. These findings highlight a gene therapy approach to treat liver cirrhosis in patients in lieu of liver transplantation and its ensuing life-long immunomodulation.
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