Less Smad2 is good for you! A scientific update on coffee's liver benefits.

Scientists at the National Institutes of Health have reported that increased coffee consumption is associated with a slower progression of fibrogenesis in patients with chronic and particularly alcoholic liver disease and a reduced incidence of heptocellular carcinoma. However, a causal mechanistic explanation was pending. New results indicate that the methylxanthine caffeine--a major component of coffee and the most widely consumed pharmacologically active substance in the world--might be responsible for this phenomenon, because it inhibits the synthesis of connective tissue growth factor (CTGF/CCN2) in liver parenchymal and nonparenchymal cells, primarily by inducing degradation of Smad2 (and to a much lesser extent Smad3) and thus impairment of transforming growth factor beta (TGF-beta) signaling. CTGF and TGF-beta play crucial roles in the fibrotic remodeling of various organs, and, ultimately, carcinogenesis. This article summarizes the clinical-epidemiological observations as well as the pathophysiological background and provides suggestions for the therapeutic use of (methyl)xanthine derivatives in the management of fibro-/carcinogenic (liver) diseases.