Biomedicines. 2026 Aug 25;14(9):1898. doi: 10.3390/biomedicines14091898.

ABSTRACT

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.

PMID:42792641 | PMC:PMC13604568 | DOI:10.3390/biomedicines14091898

Arch Bronconeumol. 2026 Sep 25:S0300-2896(26)00318-2. doi: 10.1016/j.arbres.2026.08.007. Online ahead of print.

ABSTRACT

BACKGROUND: Highly effective CFTR modulator therapy with elexacaftor-tezacaftor-ivacaftor (ETI) has revolutionized clinical outcomes in cystic fibrosis (CF), yet its effects on gut and lung microbiota, especially at the functional level, are poorly understood.

METHODS: In a 12-month prospective study, we enrolled 35 clinically stable CF patients initiating ETI. Paired fecal and sputum samples, collected at baseline and after 12 months, were analyzed using shotgun metagenomics, metaproteomics, and short-chain fatty acid (SCFA) quantification. Multi-omics data were integrated with clinical parameters assessing lung, hepatic, pancreatic, and intestinal function.

RESULTS: ETI drove significant clinical improvements, including increased ppFEV₁, higher fecal elastase, and better nutritional status, despite persistent major lung pathogens and minimal changes in liver or intestinal inflammation markers. Microbiota composition showed limited shifts: alpha diversity was stable, and beta diversity changes accounted for only small variance in both compartments. However, butyrate-producing genera enriched in feces, while oropharyngeal taxa increased in sputum. Metaproteomics revealed broad downregulation of host neutrophil-driven inflammatory proteins; sputum additionally showed increased abundance of extracellular matrix-related proteins. Microbial proteins linked to carbohydrate/lipid metabolism, particularly butanoate pathways, increased in feces alongside a trend for higher butyrate. In sputum, formaldehyde dehydrogenase enzymes rose, indicating enhanced oxidative microbial metabolism.

CONCLUSIONS: ETI is associated with minimal compositional but substantial functional reprogramming in CF microbiota. These changes are accompanied by an increase in butyrate-producing taxa, attenuation of host pro-inflammatory pathways, and a shift in lung metabolism toward oxidation. Despite ongoing pathogenic colonization, these changes suggest CFTR modulation is associated with a less inflammatory, more stable host-microbiota ecosystem.

PMID:42791132 | DOI:10.1016/j.arbres.2026.08.007

Metabolites. 2026 Aug 25;16(9):608. doi: 10.3390/metabo16090608.

ABSTRACT

With the advent of the new definition, fatty liver disorders have been reframed into metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-related liver disease (ALD), and the mixed phenotype referred to as MetALD (MASLD and increased alcohol intake). This change reflects the real-world clinical practice, where metabolic dysfunction and alcohol frequently coexist and synergize to increase risks of steatohepatitis, fibrosis, and hepatocellular carcinoma (HCC). While conventional non-invasive tests (NITs) remain the backbone of risk stratification, lipidomics and metabolomics can capture biological information on disease mechanisms and may improve early detection and prognosis. Here, we summarize the current evidence on circulating and tissue lipidomic and metabolomic signatures across MASLD, ALD and MetALD, discuss how the new definitions affect clinical risk assessment, and highlight recent studies which partially distinguish molecular fingerprints for mixed etiology disease.

PMID:42783733 | PMC:PMC13609168 | DOI:10.3390/metabo16090608