Discovery and Development of TMPRSS6 Inhibitors Modulating Hepcidin Levels in Human Hepatocytes.

Area of Science:

• Biochemistry
• Molecular Biology
• Genetics

Background:

• Iron overload disorders result from dysregulated iron absorption and storage, potentially causing organ damage.
• Hepcidin, a key regulator of iron homeostasis, is suppressed by TMPRSS6 (matriptase-2), a serine protease found in the liver.

Purpose of the Study:

• To investigate the potential of TMPRSS6 inhibitors in increasing hepcidin production for treating iron overload.

Main Methods:

• Treatment of hepatic cells (HepG2 and primary hepatocytes) with peptidomimetic and non-peptidic TMPRSS6 inhibitors.
• Assessing the impact of inhibitors on hepcidin production, HAMP gene expression, and hemojuvelin cleavage.

Main Results:

• Both peptidomimetic and optimized non-peptidic TMPRSS6 inhibitors effectively increased hepcidin production in hepatic cells.
• TMPRSS6 inhibitors were shown to inhibit TMPRSS6-dependent hemojuvelin cleavage.
• Inhibitor treatment led to increased HAMP gene expression and elevated levels of secreted hepcidin.

Conclusions:

• TMPRSS6 inhibitors represent a promising therapeutic approach for iron overload disorders.
• Targeting TMPRSS6 activity can restore hepcidin levels and improve iron regulation.