Astragali radix - Curcumae rhizoma herb pair enhances Sorafenib's efficacy by inducing ferroptosis and activates Th1 cell immune response synergistically against hepatocellular carcinoma

BACKGROUND: Sorafenib, as a first-line targeted drug for hepatocellular carcinoma (HCC), suffers from insufficient efficacy and dose-dependent toxic side effects, necessitating the development of combination therapy strategies. Clinical studies have shown that the Astragali radix - Curcumae rhizoma herb pair (ACHP) synergized with Sorafenib significantly enhanced the efficacy in advanced HCC patients, as well as improved immune function, but its synergistic mechanism remains unclear. PURPOSE: This study aimed to reveal the mechanisms by which ACHP synergistically enhances Sorafenib's anti-HCC efficacy through a dual-mode of "ferroptosis -immunomodulation", and to provide a solid theoretical basis for its clinical application. METHODS: UPLC-Q-TOF-MS/MS was employed for the component characterization of ACHP extract. In vivo and in vitro HCC models were established to evaluate the efficacy and safety of ACHP synergized with Sorafenib against HCC. Transcriptome sequencing was utilized to screen potential molecular mechanisms, while molecular biology techniques, flow cytometry and inhibitors were applied to detect ferroptosis-related markers and Th1 cell-mediated immune response markers, aiming to reveal the underlying mechanisms. RESULTS: A total of 30 components were identified from ACHP extract. Pharmacodynamic evaluations showed that ACHP synergized with Sorafenib significantly suppressed tumor growth and cell proliferation of HCC, and exhibited favorable safety. Transcriptome sequencing suggested that the anti-HCC effect of ACHP synergized with Sorafenib might involve the induction of ferroptosis and modulation of Th1/Th2 cell differentiation. Further in vivo and in vitro experiments demonstrated that ACHP enhanced Sorafenib's efficacy by regulating the xCT/GPX4 and ACSL4/ALOX15 pathways to induce lipid peroxidation-related ferroptosis. Meanwhile, ACHP activated the IL-12/STAT4 signaling axis, promoted Th1 cell differentiation and up-regulated IFN-γ secretion, and further induced M1-type macrophages polarization and IL-12 secretion, thereby strengthening the IL-12-driven positive feedback immune loop. CONCLUSION: ACHP enhances Sorafenib's efficacy by inducing lipid peroxidation-related ferroptosis and activates Th1-type anti-tumor immune responses, synergistically suppressing HCC. The study establishes a complete evidence chain of "component characterization-mechanism verification", providing novel therapeutic targets and strategic insights for the development of combination therapy for HCC.