Aquaporin-9 (aquaglyceroporin) (AQP9)

Aquaporin-9 (AQP9) is a tetrameric transmembrane channel of the aquaglyceroporin subfamily. Each monomer (~28–31 kDa) forms an independent pore built from six transmembrane helices and two conserved NPA motifs, with a wider aromatic/arginine selectivity filter (ar/R filter, ~3.4–3.5 Å) that confers broad permeability to glycerol, water, urea, lactate, hydrogen peroxide, polyols, nucleobases, and metalloids such as arsenite. It is highly expressed on the sinusoidal (basolateral) membrane of hepatocytes, where it serves as the principal pathway for glycerol uptake to fuel gluconeogenesis. AQP9 expression is regulated by nutritional and insulin states (upregulated with fasting and diabetes, downregulated by insulin). It is implicated in metabolic diseases (e.g., obesity, diabetes, fatty liver) and cancer (e.g., hepatocellular carcinoma, astrocytic tumors), making it a promising therapeutic target. Beyond its hepatic role, AQP9 also transports H2O2 (acting as a peroxiporin), lactate (potentially involved in astrocyte-to-neuron shuttle), ammonia, mannitol, selenite, and 5-fluorouracil. Small-molecule modulators of AQP9 are under exploration, but clinically approved selective inhibitors are not yet established.

Other names

AQP9Aquaporin 9Aquaglyceroporin 9Hepatic glycerol channel AQP9

Substrate transport modulation: agents or conditions that inhibit or enhance AQP9 pore conductance alter cellular entry/exit of glycerol, urea, lactate, H2O2, and xenobiotics (e.g., arsenite, 5‑FU), impacting metabolism, redox signaling, and drug sensitivity. Targeting hepatic glycerol influx to reduce gluconeogenesis and improve glycemic control (therapeutic rationale).