p-Coumaric acid inhibits hepatocellular carcinoma through promoting ROS accumulation.

Hepatocellular carcinoma (HCC) remains one of the most life-threatening diseases. The regulation of redox homeostasis plays a pivotal role in the progression of HCC. p-Coumaric acid (PCA), a naturally occurring compound, exhibits diverse pharmacological activities; however, its potential anti-HCC effects have not been previously reported. This study aimed to investigate the potential anti-HCC effects of PCA, with a focus on its role in modulating reactive oxygen species (ROS) accumulation in HCC cells. The anti-HCC effects of PCA were evaluated through in vitro and in vivo experiments. In vitro assays, including cell growth, proliferation, wound healing, and Transwell migration, assessed PCA's inhibitory effects, while flow cytometry analyzed apoptosis. Mitochondrial function and ROS levels were measured, with the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway's role explored. In vivo, a subcutaneous xenograft mouse model, using NAC as a ROS scavenger, validated PCA's effects. PCA significantly inhibited the growth and proliferation ability of HCC cells. It also impeded cell migration and induced cell shrinkage and apoptosis. Moreover, PCA suppressed the levels of anti-apoptotic and pro-proliferative proteins. From a mechanistic perspective, PCA reduced mitochondrial membrane potential and ATP production, subsequently promoting ROS accumulation. The inhibition of the Nrf2 signaling pathway by PCA further enhanced ROS levels. Hemin, an agonist of the antioxidant enzyme HO-1, counteracts the inhibitory effect of PCA on the viability of HCC cells. And, in vivo experiments demonstrated that the anti-HCC effects of PCA were reversed by N-acetylcysteine, confirming the critical role of ROS in PCA-mediated inhibition of HCC progression. Our findings indicate that PCA suppresses HCC progression by promoting ROS accumulation, suggesting its therapeutic potential for HCC.