Herein, we report two methods for the synthesis of the osteoarthritis drug rhein and its prodrug diacerein using a chemoenzymatic approach. The strategy relies on the use of an NADPH-dependent anthrol reductase of Talaromyces islandicus (ARti-2), which mediates the regioselective and reductive deoxygenation of anthraquinones. The work further implies similar biosynthesis of rhein in fungi.