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

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-derived liver phenotypes, including corrected T1 (cT1) and proton density fat fraction (PDFF), liver enzymes and clinical liver outcomes; (2) cardiometabolic endpoints; (3) 2,940 plasma proteins; (4) clinical biomarkers; and (5) 2,272 disease endpoints. Colocalization and mediation analyses were used to characterize mechanisms.

Results

Genetically proxied TMPRSS6 inhibition was associated with lower liver iron content (β = −2.50, P<0.001) and higher cT1 (β = 1.59, P<0.001), with colocalization indicating a shared causal signal. No association was observed with PDFF, liver volume, NAFLD, cirrhosis or hepatocellular carcinoma. Genetically proxied TMPRSS6 inhibition was also associated with lower C-reactive protein (β = −0.17, P<0.001), higher LDL cholesterol (β = 0.22, P<0.001) and higher coronary artery disease (CAD) risk (OR = 1.59, P<0.001), with weak colocalization of CAD with hepcidin (PP.H4 = 0.56) and LDL cholesterol (PP.H4 = 0.48). Mediation analysis suggested LDL cholesterol may account for approximately 21% (95% CI 9% to 34%) of the CAD association.

Conclusions

Human genetic evidence supports hepatic iron lowering by TMPRSS6 inhibition, but not an effect on steatosis. Higher cT1, without concordant associations with clinical liver outcomes, may reflect reduced hepatic iron rather than worsening fibroinflammation. The CAD signal, partly mediated by LDL cholesterol, warrants careful consideration in trial design.

Impact and implications

Preclinical studies have identified TMPRSS6 inhibition as a potential therapeutic strategy for metabolic liver disease, but its effects in humans and potential safety consequences remain uncertain. Using human genetic evidence, we show that genetically proxied TMPRSS6 inhibition is associated with lower hepatic iron content but not hepatic steatosis, while identifying increased coronary artery disease risk as a potential cardiovascular safety liability. These findings are relevant to researchers and drug developers pursuing TMPRSS6-directed therapies, as they suggest that clinical benefit may be more likely in patients with excess hepatic iron and highlight the importance of cardiovascular risk assessment and lipid monitoring during clinical development. As genetic proxies reflect lifelong perturbation rather than pharmacological treatment, prospective clinical studies are required to determine whether these hepatic and cardiovascular effects are reproduced with therapeutic TMPRSS6 inhibition.

Highlights

• Genetically predicted TMPRSS6 inhibition was associated with lower hepatic iron content.

• No associations were observed with hepatic steatosis or liver volume.

• Genetically predicted TMPRSS6 inhibition was associated with increased CAD risk.

• LDL-C mediated around one fifth of the CAD association.