URI alleviates tyrosine kinase inhibitors-induced ferroptosis by reprogramming lipid metabolism in p53 wild-type liver cancers.

The clinical benefit of tyrosine kinase inhibitors (TKIs)-based systemic therapy for advanced hepatocellular carcinoma (HCC) is limited due to drug resistance. Here, we uncover that lipid metabolism reprogramming mediated by unconventional prefoldin RPB5 interactor (URI) endows HCC with resistance to TKIs-induced ferroptosis. Mechanistically, URI directly interacts with TRIM28 and promotes p53 ubiquitination and degradation in a TRIM28-MDM2 dependent manner. Importantly, p53 binds to the promoter of stearoyl-CoA desaturase 1 (SCD1) and represses its transcription. High expression of URI is correlated with high level of SCD1 and their synergetic expression predicts poor prognosis and TKIs resistance in HCC. The combination of SCD1 inhibitor aramchol and deuterated sorafenib derivative donafenib displays promising anti-tumor effects in p53-wild type HCC patient-derived organoids and xenografted tumors. This combination therapy has potential clinical benefits for the patients with advanced HCC who have wild-type p53 and high levels of URI/SCD1.

Anticancer Effects of Fufang Yiliu Yin Formula on Colorectal Cancer Through Modulation of the PI3K/Akt Pathway and BCL-2 Family Proteins.

Colorectal cancer (CRC) is one of the most common malignant tumors in China. Fufang Yiliu Yin (FYY) is a traditional Chinese medicine formula used in clinical practice for cancer treatment, but its effectiveness and mechanism of action in human CRC are unclear. In this study, we investigated the antitumor effect of FYY on HCT116 and SW480 human CRC cell lines in vitro and evaluated the underlying molecular mechanism. A subcutaneous xenograft mouse model was used to confirm the antitumor effect in vivo. The components and targets of FYY were collected from the Traditional Chinese Medicine Systems Pharmacology Database (TCMSP) database. CRC targets were collected via the GeneCards and OMIM databases. Protein-protein interactions were explored using the STRING platform. Cytoscape was used to construct drug-disease-target networks. KEGG and GO analyses were performed to investigate common FYY and CRC targets. FYY significantly inhibited cell proliferation and induced HCT116 and SW480 cell apoptosis. Cell proliferation was blocked at the G0/G1 phase, while cell apoptosis was promoted at the early stage. According to the network pharmacological analysis, quercetin and kaempferol were the most bioactive compounds of FYY. The key targets of FYY were cyclin-D1, MAPK8, and EGFR. GO analysis showed that core targets included the apoptotic signaling pathway, response to steroid hormone, and cellular response to organic cyclic compound. The KEGG pathway analysis showed that FYY may affect CRC through the PI3K/Akt pathway. In vitro, FYY significantly inhibited tumor growth. Pathway analysis confirmed that FYY induced cell apoptosis by modulating PI3K/Akt signaling and BCL-2 family proteins. Hence, our findings indicate that FYY may be a promising adjuvant therapy for CRC.

Anticancer Effect of Radix Astragali on Cholangiocarcinoma In Vitro and Its Mechanism via Network Pharmacology.

BACKGROUND This study used network pharmacology method and cell model to assess the effects of Radix Astragali (RA) on cholangiocarcinoma (CCA) and to predict core targets and molecular mechanisms. MATERIAL AND METHODS We performed an in vitro study to assess the effect of RA on CCA using CCK8 assay, the Live-Cell Analysis System, and trypan blue staining. The components and targets of RA were analyzed using the Traditional Chinese Medicine Systems Pharmacology database, and genes associated with CCA were retrieved from the GeneCards and OMIM platforms. Protein-protein interactions were analyzed with the STRING platform. The components-targets-disease network was built by Cytoscape. The TIMER database revealed the expression of core targets with diverse immune infiltration levels. GO and KEGG analyses were performed to identify molecular-biology processes and signaling pathways. The predictions were verified by Western blotting. RESULTS Concentration-dependent antitumor activity was confirmed in the cholangiocarcinoma QBC939 cell line treated with RA. RA contained 16 active compounds, with quercetin and kaempferol as the core compounds. The most important biotargets for RA in CCA were caspase 3, MAPK8, MYC, EGFR, and PARP. The TIMER database revealed that the expression of caspase3 and MYC was related with diverse immune infiltration levels of CCA. The results of Western blotting showed RA significantly influenced the expression of the 5 targets that network pharmacology predicted. CONCLUSIONS RA is an active medicinal material that can be developed into a safe and effective multi-targeted anticancer treatment for CCA.