Cholesterol binding stabilizes the activated state of THIK-1 and promotes atherosclerosis.

Cholesterol stabilizes the arachidonic acid-binding pocket of THIK-1, and the THIK-1 inhibitor C101248 markedly reduces atherosclerotic plaque in Apoe-deficient mice on a high-cholesterol diet.

• Why it matters: Atherosclerosis involves cholesterol-linked activation of inflammatory signaling, but how cholesterol regulates THIK-1 and IL-1β release during plaque progression is not well defined.
• What they did: The authors used high-resolution cryo-EM to solve THIK-1 structures in apo and with arachidonic acid, halothane, C101248, and the R92S variant, then tested cholesterol effects in macrophage inflammatory assays.
• The result: Cholesterol was found to stabilize the arachidonic acid-binding pocket, amplifying arachidonic acid–induced inflammatory responses in macrophages, and THIK-1 inhibition suppressed IL-1β release and reduced plaque development in Apoe-deficient mice.

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