Formation of high molecular weight (HMW) species is a common issue encountered during manufacture of protein therapeutics. With advanced purification techniques, efficient removal of protein aggregates is no longer a challenging task, hut it is important to minimize protein aggregation level at the culture stage to reduce the downstream burden and improve overall process yield. In this regard, our recent effort on medium optimization has led us to unexpectedly discover that glucocorticoids can significantly reduce the formation of HMW species in IgG-fusion protein produced by CHO cells. First, the effectiveness of dexamethasone can he seen at nanomolar concentrations, which allows this glucocorticoid analog to be a cost-efficient chemical for reducing protein aggregation in cell cultures. Second, this reduction is mediated through glucocorticoid receptors (GR) as it is antagonized by GR antagonist RU486. Third, GR activation upregulates expression of glutathione reductase but not protein disulfide-isomerase, which may help with providing a balanced redox condition in the cells. Last, the beneficial effect of dexamethasone is not limited to one cell line, and it can be repeated in a different cell line, indicating that glucocorticoids are also applicable to other DG44 cell lines for reducing protein aggregation. (C) 2010 American Institute of Chemical Engineers Biotechnol. Prog., 26: 1417-1423, 2010