Herein, we show that (i) inflammatory cytokines and cachexia‐inducing factors (including S100B and HMGB1) induce RAGE expression in skeletal muscles; and (ii) RAGE hyperactivation plays a relevant role in the loss of muscle mass in cancer conditions principally via a p38 MAPK/myogenin/atrogin‐1 axis. This evidence concerns the gene HMGB1 and cancer.