Nonsteroidal anti-inflammatory drugs, such as ibuprofen, are known to modify salty taste perception in humans. However, the underlying molecular mechanisms remain unknown. We investigated the inhibitory effect of ibuprofen on the NaCl stimulation of epithelium sodium channel (ENaC) and transmembrane channel-like 4 (TMC4), which are involved in salty taste detection. Although ibuprofen only minimally inhibited the response of the ENaC to NaCl, it significantly inhibited the TMC4 response to NaCl with an IC 50 at 1.45 mM. These results suggest that ibuprofen interferes with detection of salty taste via inhibition of TMC4. [Display omitted] • Ibuprofen modifies salty taste perception. • ENaC and TMC4 are ion channels which involved in salt taste detection. • Ibuprofen only minimally inhibited the response of ENaC to NaCl. • TMC4 response to NaCl was significantly inhibited by ibuprofen. • Ibuprofen may interfere with salty taste perception via inhibition of TMC4. [ABSTRACT FROM AUTHOR]