Jianpi Huayu decoction enhances the antitumor effect of doxorubicin via piezo1-mediated autophagy in hepatocellular carcinoma.

[BACKGROUND] Hepatocellular carcinoma (HCC) carries a poor prognosis, especially in advanced stages. Although Piezo1, a mechanosensitive ion channel, is linked to HCC progression, its underlying mechanisms and therapeutic potential remain poorly understood.

[METHODS] Piezo1 expression in HCC and its correlation with prognosis were assessed using TCGA and GEO datasets, along with clinical tissue samples. The role of Piezo1 in HCC malignancy and autophagy was investigated in MHCC97H cells via siRNA-mediated silencing. A DEN-induced Piezo1-knockout mouse model and an shPiezo1-transfected MHCC97H xenograft nude mouse model were also used to evaluate the role of Piezo1 in tumor development and growth. The effects of Jianpi Huayu decoction (JPHY), doxorubicin (DOX), and combined treatment on malignant phenotypes and autophagy were examined in MHCC97H cells as well as an allogeneic transplantation model. Shared pathways between JPHY and DOX were identified by network pharmacology analysis and validated by molecular biology experiments. Molecular docking studies analyzed interactions between JPHY active components and Piezo1.

[RESULTS] Piezo1 was overexpressed in HCC tissues and correlated with poor prognosis. Piezo1 knockdown suppressed malignancy and enhanced autophagy in MHCC97H cells. In Piezo1 mice, the size and number of DEN-induced liver tumors were reduced by approximately 60 % and 45 %, respectively. Tumor growth was also suppressed in nude mice transplanted with shPiezo1-transfected MHCC97H cells. JPHY combined with DOX enhanced the antitumor effect and increased treatment sensitivity. Network pharmacology analysis revealed common targets of JPHY and DOX, enriched in the PI3K/AKT pathway. Both JPHY and DOX downregulated Piezo1 expression and inhibited the PI3K/AKT/mTOR pathway, while the combination demonstrated an even greater efficacy. The combination of JPHY and DOX reduced xenograft tumor size by approximately 40 % compared to DOX alone, without apparent hepatic or renal toxicity.

[CONCLUSION] This study uncovers a novel mechanism by which JPHY enhances DOX sensitivity in HCC, acting through modulation of Piezo1-mediated autophagy via the PI3K/AKT/mTOR pathway.