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

Abstract Background & Aims: Disease-modifying therapies for steatohepatitis and fibrosis remain limited. Matriptase-2 (TMPRSS6), a serine protease suppressing hepcidin to regulate iron homeostasis, is under clinical investigation for iron overload, and preclinical evidence suggests its inhibition may attenuate metabolic liver disease. Whether these effects translate to humans remains unknown. Methods: We proxied TMPRSS6 inhibition using the missense variant rs855791, weighted on circulating hepcidin. Using Mendelian randomization (MR), we assessed effects on (1) magnetic resonance imaging-deri

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