An early interventional effort in oral premalignancy requires novel molecular targets and diagnostic biomarkers to delay or reverse incidences of malignant progression. Microarray-based transcriptional profiling in disease states provides global insight into the causal biomolecular processes and novel pathways involved. In this study, we investigated transcript profiles in precancerous oral lesions to identify nearly 1,700 genes as significantly overexpressed or underexpressed and a primarily affected metabolic pathway that may be responsible for irreversible transition to progressive stages of oral cancer. For the first time, we show a convergence of several genes and pathways known for their oncogenic capabilities, in progression of premalignant oral epithelial tissues. This study consequently provides a molecular basis for persistent proinflammatory conditions in oral premalignant tissues. We found that lipocalin-type prostaglandin D2 synthase (PTGDS), a key enzyme in the arachidonic acid metabolism pathway, as repressed in premalignant stages. We show the protective role of these enzyme-derived metabolites in inhibiting cell proliferation using an in vitro oral cancer progression model. We have also confirmed the overexpression of two invasion-related biomarkers, psoriasin (PSOR1) and versican (CSPG2), in oral premalignant and malignant archival tissues. Our results clearly indicate that pharmacologic intervention with anti-inflammatory prostaglandin D2-like analogues may help prevent or delay oral epithelial carcinogenesis because of metabolic restoration of a negative feedback regulatory loop through its several cognate receptors or target molecules. Further studies directed toward a multitude of possible protective mechanisms of this lipocalin-type enzyme or its products in oral cancer progression are warranted.