Enhanced efficacy of methyl ferulate upon pentanoylation in ameliorating psoriasis via Nrf2/NF-κB pathway regulation and HDACs downregulation.

Psoriasis is a chronic autoimmune inflammatory dermatosis with a global prevalence exceeding 3%. Available therapeutic approaches for psoriasis, encompassing topical formulations, monoclonal antibodies, and phototherapy, seldom elicit full clinical remission in practice, yet are plagued by exorbitant costs or impractical administration protocols. To enhance the therapeutic efficacy of ferulic acid (FA), a widely used naturally occurring antioxidant, a series of short-chain fatty acids (SCFAs) were selected for the structural modification of FA, thereby endowing the covalent conjugate with enhanced antioxidant activity, as well as potent immunomodulatory and cell cycle regulatory properties. Using an imiquimod (IMQ)-induced psoriasis-like mouse model, pentanoylated ferulic acid methyl ester (PentFAMe) was identified as the most potent candidate compound, exhibiting the highest efficacy. Its therapeutic effects and underlying mechanism were further elucidated through in vivo and in vitro approaches. Compared with the parent compounds, the conjugate PentFAMe exhibits superior and more comprehensive pharmacological activity. The activity of PentFAMe is substantially higher than the individual component likely to be formed in vivo upon hydrolysis. Pentanoic acid alone displays potent anti-proliferative and anti-inflammatory activities via suppression of HDAC3/6 expression. PentFAMe exerts superior effects by inhibiting HDAC3/6 expression, thereby restoring acetylation levels of H3K27 and NF-κB p65. Meanwhile, PentFAMe surpassed ferulic acid in its ability to activate the antioxidant Nrf2 pathway. Furthermore, effective Nrf2 activation inhibited NF-κB phosphorylation, resulting in a notable decrease in proinflammatory cytokine and chemokine expression. PentFAMe, as a component in an oral formulation, is both cost-effective and convenient, offering a novel potential lead compound against psoriasis.