Box 1.

Potential mechanistic strategies for tackling liver fibrosis.

Promote apoptosis, senescence or reversion of hepatic myofibroblasts

  • Apoptosis

    • sulfasalazine or sulphasalazine analogues

    • CB1 antagonists

    • TIMP1 blockade using siRNA, neutralising antibody or inactive MMP9 mutants

    • HSC-specific targeted therapies

      • anti- EGFR single chain fragment variable antibody-TRAIL fusion protein

      • vitamin A-coupled liposomes to deliver siRNA against a collagen-specific chaperone

      • single chain antibody (C1–3) targeted gliotoxin

  • Senescence

    • atorvastatin

  • Reversion

    • PPAR-γ agonism or derepression

    • FXR agonists

Inhibit specific properties of hepatic myofibroblasts

  • Proliferation

    • multikinase inhibitors (e.g. gleevec, sorafenib)

  • Fibrogenesis

    • ACE inhibitors, angiotensin II receptor antagonists

    • TGF- inhibitors

    • pirfenidone

  • Contractility

    • relaxin

    • statins

    • endothelin-1 antagonists

Stimulate degradation of accumulated scar

  • TIMP1 blockade using siRNA, neutralising antibody or inactive MMP9 mutants

  • MMP gene therapy

  • Halofuginone

  • LOXL2 inhibitors

  • Cell therapies

    • autologous G-CSF mobilised CD133+ bone marrow stem cells

    • autologous CD14+ monocyte-derived macrophages

    Targeting the immune response

    • Blockade of CCL2/CCR2

    • Enhance restorative macrophages by liposome administration

    • Modulation of CXCL9/CXCR3 axis

  • ACE  angiotensin converting enzyme; CB1  cannabinoid receptor; CCL2  chemokine (C-C motif) ligand 2; CCR2; C-C chemokine receptor type 2; CXCL9  chemokine (C-X-C motif) ligand 9; CXCR3  chemokine (C-X-C motif) receptor 3; EGFR  epidermal growth factor receptor; FXR  farnesoid X receptor; G-CSF  granulocyte colony stimulating factor; HSC  hepatic stellate cell; LOXL2  lysyl oxidase-2; MMP  matrix metalloproteinases; PPAR = peroxisome proliferator-activated receptor; siRNA  small interfering RNA; TGF  transforming growth factor beta; TIMP  tissue inhibitors of metalloproteinases; TRAIL  tumour necrosis factor-related apoptosis-inducing ligand