The human papilloma virus (HPV) group comprises approximately 200 genetic types that have a special affinity for epithelial tissues and can vary from producing benign symptoms to developing into complicated pathologies, such as cancer. The HPV replicative cycle affects various cellular and molecular processes, including DNA insertions and methylation and relevant pathways related to pRb and p53, as well as ion channel expression or function. Ion channels are responsible for the flow of ions across cell membranes and play very important roles in human physiology, including the regulation of ion homeostasis, electrical excitability, and cell signaling. However, when ion channel function or expression is altered, the channels can trigger a wide range of channelopathies, including cancer. In consequence, the up- or down-regulation of ion channels in cancer makes them attractive molecular markers for the diagnosis, prognosis, and treatment of the disease. Interestingly, the activity or expression of several ion channels is dysregulated in HPV-associated cancers. Here, we review the status of ion channels and their regulation in HPV-associated cancers and discuss the potential molecular mechanisms involved. Understanding the dynamics of ion channels in these cancers should help to improve early diagnosis, prognosis, and treatment in the benefit of HPV-associated cancer patients.

Activator protein 1 (AP-1) is a family of transcription factors composed of Jun, Fos, activating transcription factor (ATF), and musculoaponeurotic fibrosarcoma (MAF) homodimers and heterodimers that regulate diverse cellular processes such as proliferation, apoptosis, differentiation, survival, and migration. Accordingly, AP-1 plays an essential role in several diseases including cancer. During liver cancer development, AP-1 abnormal activation has been implicated from cancer initiation to cancer progression. This review aims to provide a current integrative understanding of the role of AP-1 in liver carcinogenesis and suggests potential settings for its clinical use in diagnosis and treatment. Novel AP-1-based therapeutic approaches deserve further investigation and clinical application for the benefit of liver cancer patients.

Hepatocellular carcinoma (HCC) remains a major global health burden. We have recently demonstrated the synergistic cytotoxicity elicited by the combination of loratadine, raloxifene, and sorafenib in liver cancer cells. In this study, we investigated the potential mechanistic basis of this novel multi-drug regimen by identifying candidate protein targets of the three drugs. Potential protein targets of each drug were identified using the Drug Affinity Responsive Target Stability (DARTS) assay in protein extracts from the HCC cell line HuH7, and molecular docking was performed to predict binding modes and explore the structural feasibility of these drug–target interactions. Bioinformatics analyses were conducted to predict biological functions, molecular interactions, and clinical relevance. We identified 147 potential candidate DARTS-stabilized proteins for loratadine, 191 for sorafenib, and 157 for raloxifene; a proportion of these candidate proteins maintained a statistically significant association with overall survival in HCC patients: 20.14% for loratadine, 22.93% for raloxifene, and 24.47% for sorafenib. Cross-referencing with public databases confirmed several previously documented targets—complementing our experimental approach—while revealing numerous previously unreported target candidates. Docking analyses predicted favorable binding interactions between the drugs and several proteins, such as the putative complex between loratadine and N-glycanase 1 (NGLY1), whose expression correlates with reduced overall survival in HCC patients. Functional enrichment analysis showed that several targets are involved in hallmarks of cancer. Clinically relevant candidate targets of loratadine, raloxifene, and sorafenib were identified. However, as these candidate protein targets were identified exclusively in HuH7 cells, they may not fully generalize across all HCC models without further validation. Nevertheless, our results suggest that loratadine, raloxifene and sorafenib modulate key pathways involved in tumorigenesis. These findings strengthen the use of this combination as a promising therapeutic strategy for HCC and provide new opportunities for the identification of novel targets, prognostic markers, and molecular vulnerabilities suitable for pharmacological intervention in HCC and other malignancies and diseases.

Background/Objectives: Hepatocellular carcinoma (HCC) is the most prevalent primary liver tumor and is often diagnosed at advanced stages with very poor therapeutic response, leading to high mortality. Thus, new therapeutic strategies and biomarkers are urgently needed. We previously showed that the combination of loratadine, raloxifene, and sorafenib exerts synergistic cytotoxicity on HCC cells. Here, we explored potential molecular mechanisms underlying the anticancer effects of this combination using multiomics analyses. Methods: We performed proteomic analyses based on mass spectrometry, transcriptomic analyses using the Clariom D Plus human microarray (Affymetrix), and metabolomic analyses based on nuclear magnetic resonance to investigate the profile changes induced by the drug combination in HuH7 cells. Bioinformatic analyses were applied to associate the omics changes with biological functions, molecular interactions, and clinical relevance in terms of patient survival. Results: We identified several molecules whose expression changed in response to treatment across the three omics profiles analyzed. Some of them were found to be involved in hallmarks of cancer, including sustained proliferation, evasion of growth suppressors, and resistance to cell death. Integrated multi-omics analyses revealed that the drug combination suppresses critical oncogenic drivers (C7orf50, NUP188, and HS2ST1) and that the mitotic cell cycle process, DNA synthesis and cholesterol biosynthesis are the primary pathways affected. Protein–protein interaction analysis revealed five key hubs (KIF2C, PCNA, TRIP13, NDC80, and RPA3), whose expression in HCC is associated with poor clinical prognosis. Conclusions: The combined treatment rewired molecular networks involved in HCC progression. These findings identify clinically relevant molecular targets associated with poor prognosis and provide mechanistic insights into the synergistic anticancer activity of this drug combination.