Sal B-based nanoparticles suppress hepatocellular carcinoma by coordinated modulation of the PI3K-AKT-mTOR axis and direct targeting of LC3BOA

Background:Hepatocellular carcinoma(HCC)is characterized by high malignancy and therapeutic resistance.Salvianolic acid B(Sal B)exhibits antitumor activity,but its underlying molecular mechanisms in HCC remain unclear.Methods:Network pharmacology,quantitative proteomics,molecular docking,biolayer interferometry(BLI),and molecular dynamics simulations were integrated to investigate the anti-HCC mechanism of Sal B.Western blotting and in vivo tumor experiments were further performed.In addition,a liposomal nanoplatform(SalB/ICG@Lip)was developed to improve delivery efficiency.Results:Integrated analysis identified macrophage migration inhibitory factor(MIF)as a potential upstream regulatory target of Sal B.Sal B suppressed the PI3K–AKT–mTOR signaling pathway by reducing MIF expression and decreasing PI3K and AKT phosphorylation.Meanwhile,BLI and computational analyses supported a potential interaction between Sal B and LC3B.Sal B also reduced phosphorylation of mTOR,ULK1,and TFEB while increasing the LC3B-II/I ratio,suggesting enhanced autophagic activation.Moreover,SalB/ICG@Lip exhibited improved cellular uptake and enhanced antitumor efficacy in vivo with favorable biosafety.Conclusion:Sal B suppresses HCC progression through coordinated regulation of the PI3K-AKT-mTOR axis and autophagy-related pathways.The SalB/ICG@Lip nanoplatform further enhances therapeutic efficacy,supporting the potential of Sal B–based nanotherapeutic strategies for HCC treatment.