ROCK2 inhibition attenuates profibrogenic immune cell function to reverse thioacetamide-induced liver fibrosis

Area of Science:

• Immunology
• Hepatology
• Pharmacology

Background:

• Liver fibrosis, a major cause of morbidity in chronic liver disease, stems from excessive myofibroblast activation and scarring driven by pro-inflammatory cytokines.
• Rho-associated kinase 2 (ROCK2) plays a crucial role in fibrotic pathways, including inflammation and extracellular matrix remodeling, making it a potential therapeutic target.

Purpose of the Study:

• To investigate the efficacy of the selective ROCK2 inhibitor KD025 in preventing and treating liver fibrosis.
• To elucidate the impact of ROCK2 inhibition on immune cell composition and function in the context of liver fibrosis.

Main Methods:

• Utilized a thioacetamide-induced liver fibrosis model in rodents.
• Administered the selective ROCK2 inhibitor KD025 prophylactically and therapeutically.
• Analyzed immune cell composition, cytokine production, and key signaling pathways (STAT3/cofilin) in liver tissues.

Main Results:

• KD025 administration effectively attenuated liver fibrosis and promoted fibrotic regression.
• ROCK2 inhibition disrupted pro-inflammatory macrophage function by downregulating STAT3/cofilin signaling, reducing TNF-alpha production, and inhibiting migration.
• Treatment led to reduced immune cell infiltrates, decreased levels of RORγt and Bcl6, and diminished IL-17, splenic germinal centers, and serum IgG.

Conclusions:

• ROCK2 inhibition prevents and reverses liver fibrosis through direct and indirect modulation of macrophage function.
• The study highlights the therapeutic potential of targeting ROCK2 in chronic liver disease, particularly in addressing IL-17 and antibody-driven fibrogenesis.
• ROCK2 inhibition impacts key pathways including STAT3/cofilin signaling and immune cell dysregulation contributing to liver fibrosis.