The Role of Ferroptosis and Cuproptosis in Curcumin against Hepatocellular Carcinoma

Abstract

Background: Among cancer-related deaths, hepatocellular carcinoma (HCC) ranks fourth, and traditional Chinese medicine (TCM) treatment is an important complementary alternative therapy for HCC. Curcumin is a natural ingredient extracted from Curcuma longa with anti-HCC activity, while the therapeutic mechanisms of curcumin remain unclear, especially on ferroptosis and cuproptosis. Methods: Differentially expressed genes (DEGs) of curcumin treatment in PLC, KMCH, and Huh7 cells were identified, respectively. The common genes among them were then obtained to perform functional enrichment analysis and prognostic analysis. Moreover, weighted gene co-expression network analysis (WGCNA) was carried out for the construction of the co-expression network. The ferroptosis potential index (FPI) and the cuproptosis potential index (CPI) were subsequently used to quantitatively analyze the levels of ferroptosis and cuproptosis. Finally, single-cell transcriptome analysis of liver cancer was conducted. Results: We first identified 702, 515, and 721 DEGs from curcumin-treated PLC, KMCH, and Huh7 cells, respectively. Among them, HMOX1, CYP1A1, HMGCS2, LCN2, and MTTP may play an essential role in metal ion homeostasis. By WGCNA, grey60 co-expression module was associated with curcumin treatment and involved in the regulation of ion homeostasis. Furthermore, FPI and CPI assessment showed that curcumin had cell-specific effects on ferroptosis and cuproptosis in different HCC cells. In addition, there are also significant differences in ferroptosis and cuproptosis levels among 16 HCC cell subtypes according to single-cell transcriptome data analysis. Conclusions: We developed CPI and combined it with FPI to quantitatively analyze curcumin-treated HCC cells. It was found that ferroptosis and cuproptosis, two known metal ion-mediated forms of programmed cell death, may have a vital effect in treating HCC with curcumin, and there are significant differences in various liver cancer cell types and curcumin treatment which should be considered in the clinical application of curcumin.

E2F-1 inhibits ferroptosis in osteosarcoma cells by activating the PSAT1/Xct/GPX4 signaling axis

“…Multiple drugs and molecules have been shown to be effective in inhibiting osteosarcoma progression by inducing ferroptosis. Liu et al found that synthetic analogues of curcumin induced ferroptosis by increasing MDA levels, ROS levels, and intracellular iron ion levels 30 . Wen et al found that baicalin induced ferroptosis in osteosarcoma through a novel Nrf2/xCT/GPX4 regulatory axis 31 .…”

Ferroptosis in Liver Disease: Natural Active Compounds and Therapeutic Implications

“…Bioinformatics analysis is widely used to explore the complex mechanisms and effective targets of drug treatment. According to the analysis of relevant data, dehydroabietic acid [ 239 ], curcumin [ 240 ], and Astragalus membranaceus [ 241 ] could exert their potential effect in treating HCC by regulating ferroptosis-related genes or pathways. It is expected that more effective targets will be identified with the development of various omics techniques and analytical methods.…”

Human diet‐derived polyphenolic compounds and hepatic diseases: From therapeutic mechanisms to clinical utilization

“…Furthermore, several emerging molecular mechanisms related to curcumin's treatment of HCC should be mentioned. (Liu et al, 2023). Moreover, curcumin has been shown to reduce HCC resistance to lenvatinib by modulating the EGFR signaling pathway (Miyazaki et al, 2023).…”

“…Zhu et al suggested that curcumin inhibited HCC metastasis by modulating the TET1/Wnt/β‐catenin signaling pathway (J. Zhu, Qu, et al, 2022). Liu et al proposed that curcumin induced ferroptosis and cuproptosis in HCC cells to inhibit tumor development (Liu et al, 2023). Moreover, curcumin has been shown to reduce HCC resistance to lenvatinib by modulating the EGFR signaling pathway (Miyazaki et al, 2023).…”