Background: Hypoxia plays a key role in cancer progression, mainly by stabilizing and activating hypoxia-inducible factor-1 (HIF-1). For HIF-1 to function under low oxygen conditions, it must interact with the transcriptional coactivator p300, a critical step for promoting cancer cell survival and adaptation in hypoxic environments. Methods: Consequently, we used drug design and molecular simulation techniques to screen phytochemical databases, including traditional Chinese and African medicine sources, for compounds that could disrupt the p300/HIF-1 interaction. Results: In this study, we identified potential compounds with high docking scores such as EA-176920 (−8.719), EA-46881231 (−8.642), SA-31161 (−9.580), SA-5280863 (−8.179), NE-5280362 (−10.287), NE-72276 (−9.017), NA-11210533 (−10.366), NA-11336960 (−7.818), TCM-5281792 (−12.648), and TCM-6441280 (−9.470 kcal/mol) as lead compounds. Furthermore, the compound with the highest docking score from each database (EA-176920, SA-31161, NE-5280362, NA-11210533, and TCM-5281792) was subjected to further analysis. The stable binding affinity of these compounds with p300 was confirmed by Post-simulation binding free energy (−22.0020 kcal/mol, −25.4499 kcal/mol, −32.4530 kcal/mol, −33.9918 kcal/mol, and −57.7755 kcal/mol, respectively) and KD analysis. Moreover, the selected compounds followed the Lipinski rules with favorable ADMET properties like efficient intestinal absorption, high water solubility, and no toxicity. Conclusions: Our findings highlight the potential of natural compounds to target key protein–protein interactions in cancer and lay the groundwork for future in vitro and in vivo studies to explore their therapeutic potential. Specifically, disrupting the p300/HIF-1 interaction could interfere with hypoxia-driven pathways that promote tumor growth, angiogenesis, and metastasis, offering a promising strategy to suppress cancer progression at the molecular level.

Background: Hepatocellular carcinoma (HCC) is one of the most common and fatal malignancies worldwide, characterized by remarkable molecular heterogeneity and poor clinical outcomes. Despite advancements in diagnosis and treatment, the prognosis for HCC remains dismal, largely due to late-stage diagnosis and limited therapeutic efficacy. Therefore, there is a critical need to identify novel therapeutic targets and explore alternative strategies, such as drug repurposing, to improve patient outcomes. Methods: In this study, we employed network pharmacology, molecular docking, and molecular dynamics (MD) simulations to explore the potential therapeutic targets of Nirmatrelvir in HCC. Results: Nirmatrelvir targets were predicted through SwissTarget (101 targets), SuperPred (1111 targets), and Way2Drug (38 targets). Concurrently, HCC-associated genes (5726) were retrieved from DisGeNet. Cross-referencing the two datasets identified 29 overlapping proteins. A protein–protein interaction (PPI) network constructed from the overlapping proteins was analyzed using CytoHubba, identifying 10 hub genes, with HDAC1, HDAC3, and STAT3 achieving the highest degree scores. Molecular docking revealed a strong binding affinity of Nirmatrelvir to HDAC1 (docking score = −7.319 kcal/mol), HDAC3 (−6.026 kcal/mol), and STAT3 (−6.304 kcal/mol). Moreover, Nirmatrelvir displayed stable dynamic behavior in repeated 200 ns simulation analyses. Binding free energy calculations using MM/GBSA showed values of −23.692 kcal/mol for the HDAC1–Nirmatrelvir complex, −33.360 kcal/mol for HDAC3, and −21.167 kcal/mol for STAT3. MM/PBSA analysis yielded −17.987 kcal/mol for HDAC1, −27.767 kcal/mol for HDAC3, and −16.986 kcal/mol for STAT3. Conclusions: The findings demonstrate Nirmatrelvir’s strong binding affinity towards HDAC3, underscoring its potential for future drug development. Collectively, the data provide computational evidence for repurposing Nirmatrelvir as a multi-target inhibitor in HCC therapy, warranting in vitro and in vivo studies to confirm its clinical efficacy and safety and elucidate its mechanisms of action in HCC.

Numerous studies have reported that increased interleukin 6 (IL-6) and soluble IL-6 receptor (sIL-6) levels induce inflammatory conditions. However, the exact mechanisms by which IL-6 drives inflammatory conditions remain unclear. Therefore, we investigated the potential role of IL-6/sIL-6R in inducing energy metabolism, including glycolysis, oxidative phosphorylation, lactate secretion and Akt/mTOR phosphorylation, in Jurkat cells, and whether IL-6 would increase the risk of developing inflammatory conditions due to the high metabolic profile of the T cells. Jurkat CD4 T-cell lines were stimulated with IL-6/sIL-6R for 24 h prior to 48-h stimulation with anti-CD3/CD28. Lactate secretion, glycolysis and oxidative phosphorylation levels were characterized using the Seahorse XF analyser. The Akt and mTOR phosphorylation status was detected using Western blotting. IL-6/sIL-6R significantly induced glycolysis and oxidative phosphorylation and their related parameters, including glycolytic capacity and maximal respiration, followed by significantly increased lactate secretion. Akt and mTOR phosphorylation were increased, which could have resulted from energy metabolism. Here we show that IL-6 enhanced the metabolic profile of Jurkat cells. This effect could have consequences for the metabolism-related signalling pathways, including Akt and mTOR, suggesting that IL-6 might promote T-cell energy metabolism, where T-cell hyperactivity might increase the inflammatory disease risk. The findings should be validated using studies on primary cells isolated from humans.