Hepatocyte SLCO4C1 is a cAMP uptake transporter for inhibiting lipogenesis and a therapeutic target for MASLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD), the most prevalent cause of chronic liver disease worldwide, currently lacks precision medicine treatments. SLCO4C1 acts as a transporter for endogenous compounds and xenobiotics. This study aims to investigate whether SLCO4C1 plays a regulatory role in MASLD pathogenesis and to elucidate the underlying mechanisms. Using human, mouse and cellular models, we found that hepatocyte SLCO4C1 is upregulated in MASLD patients, where it serves as a key cAMP transporter dependent on Gln463, suppressing lipogenesis through the PKA-CREB-SREBP1 pathway. Hepatocyte-specific delivery of Slco4c1 via AAV8-TBG increased hepatic cAMP levels, alleviating steatosis, inflammation, and fibrosis in MASLD male mice. Similarly, forskolin, an adenylyl cyclase activator that elevates cAMP, alleviated MASLD progression, underscoring the translational potential of targeting the SLCO4C1-cAMP signaling axis. Mechanistically, during MASLD progression, FGF21 upregulates hepatic Slco4c1 expression through activating ERK/MAPK signaling, which induces EGR1 to directly bind the Slco4c1 promoter, increasing intrahepatic cAMP levels.