Dichomitus squalens, a wood-rotting fungus, can utilize recalcitrant biomass for growth; however, the extracellular metabolic processes involved are not well understood. A systematic target analysis of D. squalens has been carried out using optimized conditions for lignocellulolysis. Seven encoded proteins and 58 metabolites that consistently exhibited altered regulation patterns were identified. The predicted regulators were then vertically combined into a comprehensive network that included entire signaling pathways involved in D. squalens. Despite the diversity of these pathways, they showed complementary cooperation among themselves, ensuring the efficiency of active biodegradation and thereby yielding energy saving for the cells. Although several hydrolytic enzymes (e.g., polysaccharide-degrading enzymes, alpha/beta-hydrolase, and peroxidases) were systematically utilized, peroxidative controllers (e.g., glyoxal oxidase and P450-oxidoreductase) were rarely generated.