PAK1 represents a novel therapeutic target for urgently needed anti-fibrotic drug development in liver fibrosis

Katherine Martin, Jim Pritchett, Aoibheann Mullan, Jessica Llewellyn, Varinder Athwal, Leo Zeef, Stuart Farrow, Charles Streuli, Neil Henderson, S. Friedman, Neil Hanley, Karen Piper Hanley

Research output: Contribution to conferenceAbstractpeer-review


Aims: Identify downstream mediators of integrin β1 (Itgb1) signalling amenable to targeting in liver fibrosis.

Methods: Hepatic stellate cells (HSCs) from Itgb1fl/fl CreER, PAK1-null or control mice were activated in vitro and analysed for fibrotic markers by qPCR and immunoblotting, migration, contraction and actin organization. Transcriptomal analysis used the Affymetrix platform. Liver fibrosis was induced in vivo by bile-duct ligation (BDL) or CCl4 injection in 1,1′-disulfanediyldinaphthalen-2-ol (IPA3) or control treated, and PAK1-null and wild-type mice. Livers were assessed for collagen by Picrosirius red and hydroxyproline assay.

Results: Itgb1-null HSCs were less fibrotic, evidenced by reduced stress fibres, contraction, migration and fibrotic markers. Transcriptomic analysis of Itgb1-null HSCs, identified group 1 PAKs involved in actin organization and motility. Inhibition of all group 1 PAKs using IPA3 arrested liver fibrosis in vivo. In vitro, PAK1 emerged as the major profibrotic isoform. A PAK1 inhibitor diminished collagen production from human HSCs. Likewise, HSCs extracted from PAK1-null mice were less fibrotic and contractile. Finally, PAK1-null mice were protected against BDL-induced liver fibrosis.

Discussion: We have shown that signalling through ITGB1 drives profibrotic signalling in liver fibrosis. However, the ubiquitous nature of ITGB1 limits its clinical translation. Through transcriptomal analysis we identified the group I PAKs as targetable downstream effectors. More specifically, we identified that inhibiting PAK1 attenuates liver fibrosis in vivo, and is a novel therapeutic target. Excitingly, clinically available drugs have PAK inhibitory activity, whilst specific PAK inhibitors are in clinical development (in cancer); both may be suitable for repositioning as anti-fibrotics.
Original languageEnglish
Number of pages5
Publication statusPublished - 9 Nov 2018


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