Metabolic reprogramming is a hallmark of cancer, including hepatocellular carcinoma (HCC). Cancer cells exhibit enhanced glucose and glutamine uptake, increased glycolysis, pentose phosphate pathway activity, de novo lipogenesis, and altered amino acid metabolism. However, the metabolic crosstalk underlying cancer progression and the strategic directions for drug development remain insufficiently synthesized. This review systematically summarizes the functional mechanisms of key signaling regulators involved in cancer metabolic reprogramming, including mammalian target of rapamycin complex 1 (mTORC1), myelocytomatosis viral oncogene homolog (c-Myc), hypoxia-inducible factor-1α (HIF-1α), activating transcription factor 4 (ATF4), nuclear factor erythroid 2–related factor 2 (NRF2), and sterol regulatory element–binding protein 1 (SREBP1). Notably, we highlight the interconnections among metabolic pathways in cancer cells and the signaling hubs that orchestrate metabolic crosstalk, which together constitute an integrated network of metabolic pathways and their regulatory signals. Metabolic targets and metabolism-directed therapeutic agents with substantial developmental potential are comprehensively summarized, providing up-to-date insights and concrete directions for metabolism-targeted cancer therapy. Encouragingly, agents such as the fatty acid synthase inhibitor TVB-2640 and the glutaminase inhibitor CB-839 have already entered clinical trials. We recognize that adverse effects on normal tissues and drug resistance driven by metabolic plasticity represent major challenges for metabolism-targeted therapies. Accordingly, we systematically summarize innovative strategies that offer new therapeutic possibilities, including targeting multiple metabolic pathways through combination therapy to enhance efficacy, combining metabolic inhibitors to overcome resistance to conventional anticancer agents, leveraging metabolic reprogramming for early cancer detection, and exploring emerging approaches such as immunometabolism and metabolomics.

Diosmetin (DIOS), a flavonoid compound, is abundant in Citrus limon. Emerging studies have shown that DIOS is an effective compound implicated in multiple types of cancer. However, whether DIOS serves a role in hepatocellular carcinoma (HCC) is still obscure. HepG2 cells were used in the present study, and it was observed that DIOS exhibited antitumor activity against liver cancer cells. Western blotting was performed to evaluate cell apoptosis and survival-associated proteins, and the results demonstrated that DIOS treatment resulted in the activation of the p53‑dependent apoptosis pathway. Our results revealed that DIOS caused inhibition of the nuclear factor (NF)‑κB signaling pathway and downregulation of Notch3 receptor. Furthermore, by using small hairpin RNA‑Notch3, it was confirmed that DIOS inhibited the NF‑κB signaling pathway by inactivation of Notch3. In conclusion, the present results demonstrated that DIOS triggered cell apoptosis by activation of the p53 signaling pathway and inhibited the NF‑κB cell survival pathway by downregulation of Notch3 receptor expression. DIOS is a potential agent for prevention of HCC.

Background: EVA1A (Eva-1 homolog A), a novel protein involved in autophagy and apoptosis, functions as a tumor suppressor in some human primary cancers, including hepatocellular carcinoma (HCC). While it is consistently downregulated in several cancers, its involvement in hepatocarcinogenesis is still largely unknown. Methods: We first detected the expression of EVA1A in HCC tissues and cell lines using RT‒qPCR, immunohistochemistry and western blotting and detected the expression of miR-103a-3p by RT‒qPCR. Then, bioinformatics prediction, dual-luciferase reporter gene assays and western blotting were used to screen and identify the upstream microRNA of EVA1A. After manipulating the expression of miR-103a-3p or EVA1A, wound healing, invasion, proliferation, colony formation, apoptosis, autophagy, mitosis and mitochondrial function assays, including mitochondrial membrane potential, ROS and ATP production assays, were performed to investigate the functions of miR-103a-3p targeting EVA1A in HCC cells. Apoptosis-related proteins were assessed by RT‒qPCR (TP53) or western blotting (TP53, BAX, Bcl-2 and caspase-3). Autophagy level was evaluated by observing LC3 puncta and examining the protein levels of p62, Beclin1 and LC3-II/I. Results: We found that EVA1A expression was decreased while miR-103a-3p expression was increased in HCC tissues and cell lines and that their expression was inversely correlated in HCC patients. The expression of miR-103a-3p was associated with HCC tumor stage and poor prognosis. miR-103a-3p could target EVA1A through direct binding to its 3'-UTR and suppress its expression. Overexpression of miR-103a-3p significantly downregulated the expression of EVA1A, TP53 and BAX, upregulated the JAK2/STAT3 pathway and promoted HCC cell migration, invasion and proliferation, while repression of miR-103a-3p dramatically upregulated the expression of EVA1A, TP53, BAX and cleaved-caspase-3, inhibited HCC cell migration, invasion and proliferation, and caused mitochondrial dysfunction and apoptosis. Overexpression of EVA1A significantly attenuated the cancer-promoting effects of miR-103a-3p in HCC cells, while knockdown of EVA1A alleviated the mitochondrial dysfunction and apoptosis caused by miR-103a-3p inhibition. Overexpression of EVA1A did not induce significant changes in autophagy levels, nor did it affect G2/M transition or mitosis. Conclusion: These findings indicate that the downregulation of the tumor suppressor EVA1A by miR-103a-3p potentially acts as a key mediator in HCC progression, mainly by inhibiting apoptosis and promoting metastasis. The miR-103a/EVA1A/TP53 axis provides a new potential diagnostic and therapeutic target for HCC treatment.