Fig 1: Schematic diagram depicting possible mechanisms involved in the anti-fibrotic effect of melatonin and PAA. Renal IRI activated TGF-ß signaling and caused renal fibrosis. Treatment with both melatonin and PAA simultaneously inhibit renal fibrosis, but the underlying mechanisms are totally different. Melatonin treatment targets multiple downstream mediators of TGF-ß signaling, including Smad2, Smad3, Smad4, Smad7, PI3K, ERK1/2, and p38, while PAA treatment attenuates renal fibrosis by selectively inhibiting Smad3 phosphorylation via disturbing the interactions of Smad3 with TGFßRI and SARA. Interestingly, PAA treatment can enhance the inhibitory effects of melatonin on Smad2 and Smad3 phosphorylation. Besides, PAA has greater inhibitory effects than melatonin on the activation of Wnt/ß-catenin signaling and downstream target genes.IRI, ischemia-reperfusion injury; PAA, poricoic acid A; PAI-1, plasminogen activator inhibitor-1; SARA, Smad anchor for receptor activation; TGF-ß, transforming growth factor-ß, TGFßRI, transforming growth factor-ß receptor II.