Hydroxy Safflower Yellow A: A Natural Compound from Carthamus tinctorius L. with Potent Activity Against Liver Fibrosis and Cancer.

Liver fibrosis represents an abnormal reparative response to chronic liver injury. Persistent fibrosis may progress to cirrhosis and ultimately lead to hepatocellular carcinoma (HCC). Hydroxy-safflower yellow pigment A (HSYA), a natural flavonoid compound with a chalcone structure extracted from Cardamum tinctorius L. (safflower), has demonstrated potential biological activities in delaying liver fibrosis and exhibiting anti-HCC effects. This review aims to comprehensively elucidate the mechanisms of action of HSYA in liver fibrosis and HCC. Literature on in vitro (cell) and in vivo (animal) studies of HSYA for treating liver fibrosis and HCC was systematically retrieved from databases including PubMed, Google Scholar, and China National Knowledge Infrastructure (CNKI), followed by rational synthesis. HSYA is a promising natural product for treating liver fibrosis and HCC. HSYA exerts anti-fibrotic effects by counteracting oxidative stress, reducing inflammation, regulating hepatic metabolism, and modulating hepatic stellate cells (HSCs). In liver fibrosis, HSYA primarily suppresses HSCs activation, induces their senescence and apoptosis, and modulates hepatic metabolism and the immune microenvironment through signaling pathways such as PPARγ/p38 MAPK, miR-29a-3p/PDGFRB, and TGF-β1/Smad3. HSYA exerts its anti-HCC effects by inducing apoptosis in hepatocellular carcinoma cells, regulating autophagy in these cells, inhibiting tumor invasion, arresting the cell cycle, and modulating the immune microenvironment. In HCC, HSYA primarily induces apoptosis in hepatocellular carcinoma cells and regulates autophagy through signaling pathways such as PI3K/Akt/mTOR, NF-κB, and ERK/MAPK, while also modulating the tumor immune microenvironment. HSYA, as a multi-target, multi-pathway natural bioactive compound, demonstrates significant potential in delaying liver fibrosis and preventing and treating liver cancer. In particular, HSYA exerts potent anti-fibrotic and anti-hepatocellular carcinoma effects by modulating key signaling pathways such as PPARγ, NF-κB, and PI3K/Akt. This mechanism likely represents the critical pathway through which HSYA effectively blocks the progression from fibrosis to HCC.