Chronic liver diseases, including cancer, are characterized by inflammation and elevated serum ferritin (SF).However, the causal-relationship remains unclear. This study used primary rat hepatic stellate cells (HSC) as amodel to investigate effects of physiological SF concentrations (10, 100 and 1000 pM) because HSCs play a centralrole in the development and progression of liver fibrosis. Physiological concentrations of SF, either horse SF orhuman serum, induced pro-inflammatory cytokine IL1β, IL6 and TNFα secretion in rat activated HSCs (allp<0.05). By contrast, treatment did not alter activation marker αSMA expression. The presence of SF markedlyenhanced expression of Grp78 mRNA (p<0.01). Furthermore, transient knock down of Grp78 by endotoxin EGFSubAabolished SF-induced IL1β and TNFα secretion in activated HSCs (all p<0.05). In conclusion, our resultsshowed that at physiological concentrations SF functions as a pro-inflammatory mediator in primary rat HSCs.We also provide a molecular basis for the action of SF and identified Grp78-associated ER stress pathways as anovel potential therapeutic target for resolution of fibrosis and possible prevention of liver cancer.