Diminishing Hepcidin via Reducing IL-6/STAT3 Pathway by Utilizing Ferulic Acid: An In Vitro Study

<b>Background/Objectives</b>: Hepcidin is a negative regulator of iron absorption that is released by hepatocytes. It is one of the main contributors to hypoferremia and anemia in inflammatory and oncological disorders that are mediated by the proinflammatory cytokine <i>IL-6</i>/STAT3 pathway. Ferulic acid (FA) is a phenolic compound with pleiotropic biological activities, including anti-inflammatory activity. However, its effect on hepcidin secretion is still unknown. Thus, this study aimed to explore the impact of FA on hepcidin levels and the underlying mechanism. <b>Methods</b>: HepG2 cells were treated with different log percentages of FA, and their viability was determined via the MTT assay. The relative expression of <i>IL-6</i> and <i>HAMP</i> in treated and untreated cells was measured via qRT-PCR, and the protein levels of hepcidin, <i>IL-6</i> and STAT3 were measured using ELISA. <b>Results</b>: The MTT test showed an inverse relationship between FA concentrations and HepG2 cell proliferation; FA's IC₅₀ value was 0.07669%. The expression levels of <i>IL-6</i> and <i>HAMP</i> were significantly increased in HepG2 cells following 24 h of culture with 4 μg/mL LPS. Meanwhile, the addition of FA significantly decreased the relative expression levels of these two genes and the secretion levels of <i>IL-6</i>, STAT3 and hepcidin compared to the cells treated with LPS alone. <b>Conclusions</b>: Overall, these findings show that FA modifies inflammatory pathways, affecting hepcidin levels via the <i>IL-6</i>/STAT3 pathway. Thus, this suggests FA as a potential therapeutic agent against the hypoferremia and anemia developed due to dysregulated hepcidin levels in diseases such as inflammatory and oncological disorders.