Paeoniflorin Ameliorates Metabolic Dysfunction-Associated Steatotic Liver Disease by SYK/SH3BP2 Signaling Pathway

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the leading cause of chronic liver disease globally and constitutes an independent risk factor for cardiovascular disease and mortality. Paeoniflorin (PF), the primary active compound derived from the traditional Chinese herb Paeonia lactiflora Pall., demonstrates multiple pharmacological activities. However, its anti-MASLD mechanisms remain incompletely elucidated. This study revealed that PF markedly ameliorates MASLD pathology by reducing hepatic lipid accumulation, inflammation, and fibrosis; ameliorating insulin resistance and liver function parameters; modulating key lipid metabolism genes (acetyl-coA carboxylase [ACC], sterol regulatory element-binding protein 1 [SREBP1], peroxisome proliferator-activated receptor gamma [PPAR-γ], fatty acid synthase [FASN], carnitine palmitoyltransferase 1 [CPT1], peroxisome proliferator-activated receptor alpha [PPAR-α], adipose triglyceride lipase [ATGL], and cluster of differentiation 36 [CD36]); decreasing pro-inflammatory factors (interleukin-1β [IL-1β], IL-6, tumor growth factor-α [TGF-α], and monocyte chemoattractant protein-1 [MCP-1]); and suppressing hepatic fibrosis markers (alpha-smooth muscle actin [α-SMA], tissue inhibitor of metalloproteinases-1 [TIMP1], collagen type I alpha 1 chain [COL1α1], fibronectin 1 [FN1], platelet-derived growth factor receptor beta [PDGFRβ], and plasminogen activator inhibitor-1 [PAI-1]). Through integrated transcriptomics and pharmacological overexpression approaches, we identified the SYK/SH3BP2 signaling pathway as the crucial mechanism driving MASLD pathogenesis. PF effectively attenuated hepatic metabolic dysregulation, inflammation, and fibrotic activation through inhibition of this pathway. Our work provided the first evidence establishing the SYK/SH3BP2 signaling axis as a pivotal pathway in MASLD progression, unveiling novel therapeutic targets while furnishing a mechanistic foundation for PF's potential application in MASLD treatment.