Chlorogenic acid induces hepatocellular carcinoma cell ferroptosis via PTGS2/AKR1C3/GPX4 axis-mediated reprogramming of arachidonic acid metabolism.

BACKGROUND: Ferroptosis is an iron-dependent programmed non-apoptotic cell death characterized by the accumulation of free iron ions and lipid peroxidation. It is associated with the inactivation of glutathione peroxidase (GPX) and the accumulation of lipid peroxides within cells. Ferroptosis is closely related to the occurrence and development of hepatocellular carcinoma (HCC). Chlorogenic acid (CGA), an important bioactive component found in 61 traditional Chinese medicines such as Eucommia ulmoides, has been extensively studied for its effects on various malignant tumors. However, the specific role and potential mechanism of CGA in HCC remain unclear. AIM: To elucidate the anti-tumor characteristics and potential mechanisms of CGA in inducing ferroptosis in HCC cells. METHODS: The effects of CGA on the proliferation, migration, and invasion of HCC cells were evaluated through in vitro experiments. Bioinformatics analysis combined with network pharmacology was used to study the potential targets and molecular mechanisms of CGA intervention in HCC ferroptosis. In vitro experiments were conducted to verify and explore the anti-HCC effects and mechanisms of CGA through the ferroptosis pathway. RESULTS: In vitro experiments showed that CGA dose-dependently inhibited the proliferation, invasion, and migration of HCC cells. Bioinformatics analysis combined with network pharmacology revealed that the pathway of CGA intervention in HCC cell ferroptosis was mainly enriched in the prostaglandin endoperoxide synthase 2 (PTGS2)/aldo-keto reductase family 1 member C3 (AKR1C3)/GPX4 signaling pathway, which was associated with arachidonic acid. In vitro experiments further confirmed that CGA-induced ferroptosis in HCC cells was related to mitochondrial damage through the reprogramming of arachidonic acid metabolism by regulating the PTGS2/AKR1C3/GPX4 signaling pathway. CONCLUSION: This study demonstrates that CGA inhibits HCC cell proliferation, migration, and invasion by inducing ferroptosis through the PTGS2/AKR1C3/GPX4 axis, suggesting its potential as a novel ferroptosis inducer or anti-HCC drug.