TMP: A dual modulator of apoptosis and autophagy via SHP-1 regulation in hepatocellular carcinoma

Background: Hepatocellular carcinoma (HCC) poses a significant health burden due to its high incidence, and current treatment effectiveness is hindered by drug resistance. Thus, investigation of novel therapeutic approaches derived from natural sources is crucial for improving patient outcomes. Aims: This study aimed to explore the potential of Tetramethylpyrazine (TMP), bioactive alkaloid (ligustrazine) isolated from Chuanxiong (Ligusticum Wallichii), in targeting HCC by inducing apoptosis and enhancing autophagy. The study focused on elucidating the molecular mechanisms underlying anti-cancer effects of TMP. Main methods: To determine the influence of TMP on apoptosis and autophagy, Western blot analysis, annexin V assay, cell cycle analysis, acridine orange staining, and immunocytochemistry were performed. Next, the activation of the STAT3 signaling pathway and the anti-cancer effects of TMP in vivo were examined in an orthotopic HCCLM3-Lu mouse model. Key findings: TMP treatment induced apoptosis in HCCLM3 and Hep3B cells by activating key apoptotic factors while inhibiting proteins associated with cell survival and angiogenesis. Additionally, TMP enhanced autophagy by promoting the formation of autophagosomes and stimulating autophagy-related proteins. Furthermore, TMP suppressed the activation of the STAT3 signaling pathway by upregulating SHP-1, thereby inhibiting tumorigenesis and activating cell death pathways. Additionally, our in vivo research demonstrated that TMP significantly inhibited tumor growth and triggered the activation of both apoptosis and autophagy in tumor tissues. Significance: Our findings of this study demonstrate that TMP exerts a dual-action mechanism by modulating both apoptosis and autophagy, thus offering a promising strategy to overcome drug resistance in HCC.