A Proanthocyanidins-Rich Cili (Rosa roxburghii) Fruit Extract Protects CCl4-Induced Mouse Hepatic Fibrosis via Modulation of Ferroptosis and Gut Microbiota

Background: Cili (Rosa roxburghii Tratt) is a unique fruit native to China’s Yunnan–Guizhou Plateau, rich in vitamin C, polyphenols, and triterpene, with broad health-promoting effects. Although cili’s hepatoprotective properties are reported, the bioactive components and underlying mechanisms remain poorly defined. Methods: We enriched proanthocyanidins from cili using column chromatography, identified their components via UPLC-Q-TOF-MS/MS, and validated their anti-liver fibrosis effects through in vitro and in vivo experiments. Results: Herein, we developed a novel proanthocyanidin-rich cili fruit extract (PACs-CFE) containing 84.2% total proanthocyanidins, comprising catechins, epicatechins, and diverse B-type dimers, trimers, tetramers, and gallate esters, as characterized by UPLC-Q-TOF-MS/MS. PACs-CFE inhibited LX-2 activation, suppressed collagen III and α-SMA expression, and induced ferroptosis via mitochondrial injury, reactive oxygen species accumulation, and GPX4/ferritin downregulation. In vivo, PACs-CFE ameliorated liver fibrosis, restored hepatic architecture, and improved serum alanine aminotransferase, aspartate aminotransferase, and bilirubin profiles. Moreover, PACs-CFE modulated the TGF-β1/Smad3 signaling pathway and beneficially reshaped the gut microbiota, enriching anti-inflammatory and hepatoprotective genera while reducing pathogenic taxa. Conclusions: Our findings show that PACs-CFE exerts multi-targeted anti-fibrotic effects through hepatic stellate cell inactivation, ferroptosis induction, TGF-β1/Smad3 suppression, and gut–liver axis modulation. This study provides useful insight into the hepatoprotective potential of cili fruit and supports its development as standardized functional ingredients for liver health.