Human genetic investigation of TMPRSS6 as a therapeutic target for liver disease: efficacy and safety liabilities

Genetically proxied TMPRSS6 inhibition is linked to lower liver iron content (β = -2.50, P<0.001) and higher corrected T1 (β = 1.59, P<0.001) in humans.

• Why it matters: Disease-modifying options for steatohepatitis and fibrosis are limited, and it is unclear whether TMPRSS6 inhibition’s preclinical metabolic liver benefits translate to human liver biology and safety.
• What they did: Using Mendelian randomization with the missense variant rs855791 weighted on circulating hepcidin, the study tested MRI liver traits, liver enzymes, clinical outcomes, and additional cardiometabolic and biomarker endpoints.
• The result: TMPRSS6 inhibition showed no association with PDFF, liver volume, NAFLD, cirrhosis, or hepatocellular carcinoma, while it was associated with CAD risk (OR = 1.59, P<0.001) partly mediated by LDL cholesterol (~21%, 95% CI 9% to 34%).

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