Rosavin

Rhodiola crenulata (Hook. f. & Thomson) H. Ohba is a medicinal plant known for its prominent hepatoprotective and immunomodulatory properties. Rosavin (RSV), a phenylpropanoid glycoside isolated from its roots, exhibits regulatory effects on hepatic inflammation.

This study elucidates the hepatoprotective activity of RSV and its underlying mechanism in hepatic fibrosis.

C57BL/6 mice were pretreated with thioacetamide (TAA) prior to RSV administration. RNA sequencing analyzed related signaling pathways. Hepatocyte inflammatory injury models were established by treating LX-2 with TGF-β, and HepG2 with TNF-α. Murine peritoneal macrophages (MPMs) were stimulated in vitro with LPS/ATP. To evaluate the functional role of Kruppel-like factor 14 (KLF14), siKLF14 was transfected into LX-2, HepG2, and MPMs. Dual-luciferase reporter assays verified the interaction between KLF14 and the P2X7r promoter.

RNA sequencing identified the NOD-like receptor/neutrophil extracellular traps (NETs) signaling pathway is essential for RSV-mediated hepatoprotection against TAA-induced liver injury in mice. RSV upregulated KLF14 expression while downregulating the P2X7r-NLRP3 pathway and its target genes. Silencing of KLF14 by siRNA markedly upregulated P2X7r expression at both mRNA and protein levels in mouse liver, thereby aggravating hepatic inflammatory responses. Deficiency of KLF14 in LX-2, HepG2, and MPMs impaired the inhibitory effect of RSV on the P2X7r-NLRP3 pathway. KLF14 might bind to the P2X7r promoter. Additionally, RSV reduced pyroptosis in MPMs, attenuating the inflammatory.

RSV attenuated the inflammatory response via the KLF14-P2X7r/NLRP3 pathway and inhibited fibrogenesis, suggesting RSV as a potential therapeutic agent for hepatic fibrosis.

Rosavin, a characteristic component of Rhodiola rosea L., exhibits various pharmacological activities, including antioxidant and anti-inflammatory effects. However, its role in alcoholic fatty liver disease (AFLD) remains unclear. The aim of this study was to investigate the protective effects of Rosavin against AFLD and to elucidate its underlying molecular mechanisms. In this study, Rosavin (25 μM and 50 μM for in vitro; 100 and 200 mg/kg/d via oral gavage for 10 days in vivo) was found to significantly mitigate alcohol-induced hepatic lipid accumulation, enhance antioxidant capacity, and alleviate liver injury, demonstrating its protective effects against AFLD both in vitro and in vivo. Through network pharmacology and molecular docking, six potential targets of Rosavin in AFLD were identified: nitric oxide synthase 3 (NOS3), proto-oncogene tyrosine-protein kinase Src (SRC), peroxisome proliferator-activated receptor gamma (PPARG), mitogen-activated protein kinase 14 (MAPK14, also known as p38α), tumor necrosis factor alpha (TNFα), and insulin-like growth factor 1 (IGF-1). RT-qPCR and western blotting confirmed that Rosavin downregulates PPARG, TNFα, and IGF-1 expression and suppresses p38 phosphorylation. Rescue experiments further revealed that the suppressive effect of Rosavin on PPARG expression is reversed by the PPARG-specific agonist Mesalazine, which not only counteracts the protective effects of Rosavin but also reverses Rosavin-induced changes in MAPK14 and IGF-1 expression. In conclusion, Rosavin alleviates AFLD by downregulating PPARG and subsequently modulating the MAPK14 and IGF-1 signaling pathways. This study provides the first evidence that Rosavin protects against AFLD via PPARG, highlighting its potential as a therapeutic agent for AFLD treatment.