Journal of molecular medicine (Berlin, Germany)最新文献

{"title":"Bystander effects in photodynamic therapy-treated tumors involve spatiotemporally extended ferroptosis.","authors":"Mladen Korbelik, Albert W Girotti, David Kessel","doi":"10.1007/s00109-026-02651-3","DOIUrl":"10.1007/s00109-026-02651-3","url":null,"abstract":"<p><p>The tumor bystander effect describes the ability of cells sustaining therapeutic treatment damage to transmit distress signals to neighboring unharmed cells and change their behavior. Photodynamic therapy (PDT), which uses light for activation of photosensitizing drugs in targeted lesions to produce cytotoxic damage, is one of the cancer treatment modalities inducing highly robust bystander effects. This is caused to a large extent by the propensity of PDT for creating extensive lipid peroxidation damage and related instigation of ferroptotic cell death. Lipid peroxides appear to be major participants in intercellular signaling generating the bystander effect and orchestrating ferroptosis that appears to have a pivotal role in propagating the lethal (therapeutically beneficial) form of bystander response. In contrast, nitric oxide (NO) released from PDT-treated cancer cells has emerged as a major signal for therapeutically detrimental bystander effects due to promoting tumor growth and metastasis. It is becoming increasingly evident that exploiting the bystander response can be an attractive strategy for improving tumoricidal depth with consequently elevated tumor cure rates following PDT treatment. A two-pronged approach is proposed for achieving this goal: (i) inactivating iNOS enzyme with a specific pharmacologic inhibitor, and (ii) amplifying the induction of cytotoxic ferroptosis in nearby cells initially unaffected by photodamage, thereby limiting their ability to promote tumor expansion.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":"43"},"PeriodicalIF":4.2,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146160024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Galectin-9 potentiates salivary gland damage by inducing ferroptosis in Sjogren's disease.","authors":"Fangyu Liu, Tiantian Deng, Yan Zhang, Xuanyi Zhou, Zihan Liu, Haojia Zhao, Jiahui Tang, Jing Luo, Qingwen Tao, Zihan Wang","doi":"10.1007/s00109-026-02649-x","DOIUrl":"10.1007/s00109-026-02649-x","url":null,"abstract":"<p><p>Sjögren's disease (SjD), a systemic autoimmune disease, is characterized by exocrine glandular damage and hypofunction. The molecular mechanism of SjD was still unknown. Mendelian analysis was conducted to identify the targets. Clinical characteristics of the serum protein were assessed in a cohort of SjD patients. In NOD mice, the target inhibitor was used to regulate lymphocytic infiltration and salivary secretion, and RNA-seq was conducted. Ferroptosis-related characters and salivary glandular function were evaluated in target-treated animals, as assessed by Fer-1 rescue. As the results indicated, Mendelian analysis identified LGALS9 (the gene encoding Gal9) as a key gene for SjD. In patients, clustering of CRP, ESR, IgG, and RF distinguished two patient groups with distinct Gal9 levels. Elevated Gal9 levels correlated with decreased unstimulated whole saliva flow and higher focus scores. GSE datasets showed that Gal9 is associated with the ferroptosis markers. In the NOD model, Gal9 inhibition reduced FS and IgG levels as well as decreased Th1 and Th17 infiltration. RNA-seq revealed enrichment of ferroptosis-related pathways in SjD. As a regulator of glutathione metabolism, Gal9 promotes ferroptosis through IFN-γ-dependent regulation of ACSL4 and GPX4. Meanwhile, the exacerbation of glandular injury and lipid peroxidation induced by Gal9 was abolished by ferroptosis inhibitor Fer-1. In conclusion, Gal9 promoted ferroptosis-related salivary gland dysfunction in SjD. KEY MESSAGES: Galectin9 (Gal9) acts as a pathogenic mediator in Sjögren's disease (SjD) and a mechanistic amplifier of ferroptosis. Gal9 identified as an upstream inducer of ferroptosis, exacerbated the lymphocytic infiltration and glandular dysfunction in SjD. Inhibition of ferroptosis can restore Gal9-induced salivary gland dysregulation.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":"42"},"PeriodicalIF":4.2,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146152225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spinal fluid antibody profile against bacteria demonstrates intrathecal antibody production in demyelinating diseases.","authors":"Emily E Polidoro, Nicholas Stosiek, Jon D Laman, Cheryl A Palmer, John D Kriesel","doi":"10.1007/s00109-025-02616-y","DOIUrl":"10.1007/s00109-025-02616-y","url":null,"abstract":"<p><p>This study follows work establishing multiple sclerosis (MS) microbial candidates from RNA sequencing of human brain samples. A subsequent study demonstrated anti-microbial immune responses in cerebrospinal fluid (CSF) of patients with demyelinating diseases (DD) and other neurologic diseases (OND). We aim to expand evidence for specific anti-microbial responses in CSF of patients with DD. CSF IgG ELISA assays were developed from 20 bacteria identified as MS microbial candidates. CSF responses from patients with DD (N = 16) and OND (N = 8) were determined using commercial CSF as positive and negative controls. CSF reactivity was expressed as ELISA Index (EI) values against each of the lysates. Antibody Index (AI) values were determined by comparing CSF reactivity and diluted serum samples with equivalent IgG concentrations. AI values > 1.5 were considered positive, 1.0-1.49 equivocal, and < 1.0 negative. Most samples from both groups displayed reactivity across all 20 lysates, with an overall rate of 87.8%. CSF EI values were highest against Haemophilus, Aggregatibacter, and Streptococcus, lowest against Veillonella, Fusobacterium, and Alistipes. Twenty-five percent of subjects with DD and 13% with OND had AI > 1.5 to at least one lysate. Clustering of AI values from four DD samples against Bacteroides and Lactobacillus was observed. This serological study shows reactivity against multiple bacteria in CSF from patients with primary DD including MS and OND. Elevated AI in four DD and one OND subject provides evidence for specific intrathecal antibody production in these patients. KEY MESSAGES: This study measured humoral immune responses in the cerebrospinal fluid (CSF) of human subjects with multiple sclerosis (MS) and other demyelinating diseases against 20 candidate bacteria previously identified by sequencing of diseased human brain tissue. The method described here involves diluting CSF to match the serum IgG concentrations, running an ELISA, and calculating an Antibody Index (AI). The methods described here are improved by directly measuring banked CSF and serum IgG concentrations in the laboratory. Several subjects with demyelinating diseases clustered strongly for responses against Bacteroides, Lactobacillus, Akkermansia, and Alistipes, found in the normal flora in the human gut and female genital tract.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":"41"},"PeriodicalIF":4.2,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12876083/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146129213","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated regulation of ferroptosis in prostate cancer covering mechanisms, resistance, and translational opportunities.","authors":"Zhihong Wang, Guo Chen, Zhihong Liu","doi":"10.1007/s00109-026-02641-5","DOIUrl":"10.1007/s00109-026-02641-5","url":null,"abstract":"<p><p>Ferroptosis, an iron dependent form of regulated cell death driven by lipid peroxidation, has emerged as a pivotal process in prostate cancer biology and therapy. This review summarizes the multifaceted regulation of ferroptosis in prostate cancer from molecular, metabolic, and microenvironmental perspectives. Core regulators such as GPX4, SLC7A11, and ACSL4 coordinate redox balance, glutathione metabolism, and lipid peroxidation, together determining ferroptotic sensitivity. Transcriptional, epigenetic, and post translational mechanisms including STAT3, the JMJD6 ATF4 axis, and TRIM family proteins further refine ferroptosis regulation. Metabolic reprogramming involving APOC1, SLC25A10, and BCAT2, as well as mitochondrial dynamics governed by VSTM2L and RPS6KC1, establishes metabolic dependencies that influence resistance or susceptibility to ferroptosis. Within the tumor microenvironment, cancer-associated fibroblasts and extracellular matrix components modulate ferroptosis through lactate signaling, exosomal microRNAs, and detachment resistance. Clinically, ferroptosis-related gene signatures provide valuable prognostic tools and predict responses to radiotherapy, antiandrogen therapy, and immunotherapy, linking ferroptotic dysregulation with immune suppression and treatment resistance. Emerging therapeutic strategies that inhibit GPX4 or system Xc-, modulate iron metabolism, and employ PSMA-targeted nanoplatforms have shown potent antitumor efficacy, especially in castration resistant disease. Repurposed drugs such as flubendazole and the ezetimibe derivative L14-8, along with natural compounds including evodiamine and luteolin, demonstrate translational potential for ferroptosis induction. Collectively, ferroptosis represents a promising therapeutic vulnerability for precision treatment of advanced prostate cancer.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":"40"},"PeriodicalIF":4.2,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146121707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Liver specific-inhibition of LPCAT3 ameliorates metabolic dysfunction-associated steatotic liver disease.","authors":"Vijay Kondreddy, Ramchandra Reddy Jala, Jhansi Magisetty","doi":"10.1007/s00109-026-02648-y","DOIUrl":"10.1007/s00109-026-02648-y","url":null,"abstract":"<p><p>The membrane unsaturation in the liver is associated with abnormal biosynthesis and accumulation of cholesterol and triglycerides, which is a hallmark of metabolic dysfunction-associated steatotic liver disease (MASLD). The lysophosphatidylcholine acyltransferase 3 (LPCAT3) incorporates arachidonic acid (AA) into the membrane phospholipids and increases the degree of unsaturation. The metabolites of AA are involved in the lipogenesis under high nutrient conditions. However, the mechanistic insights by which LPCAT3 contribute to lipogenesis and MASLD remain unknown. This study found that LPACT3 is upregulated in the liver tissues of diet-induced MASLD and associated with a prominent increase in the arachidonic acid content in the liver, expression of lipogenic genes, and enlargement of liver cells filled with lipid droplets. Most importantly, the prostaglandin E₂ (PGE₂) was notably elevated in the plasma of the high-fat-fed mice. Gene silencing of LPCAT3 notably depleted the AA and PGE₂ in the hepatocytes and attenuated the high-palmitic acid and glucose-induced accumulation of triglycerides and cholesterol. Exogenous addition of PGE₂ markedly reversed the reduced triglyceride and cholesterol accumulation in the LPCAT3 silenced cells. These results indicate that the LPCAT3-arachidonic acid-PGE₂ axis plays a crucial role in lipogenesis in response to excess nutrients in the liver. Most importantly, targeted pharmacologic therapy using GalNac-LPCAT3 siRNA specifically inhibits LPCAT3 expression in the liver and protects against high-fat-induced inflammation, lipogenesis and hepatic dysfunction without affecting hepatic VLDL secretion. This GalNAc-LPCAT3 siRNA biomimetic combined represented safe, effective, and versatile carriers for developing hepatocyte-specific gene therapeutics and preventing MASLD.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":"39"},"PeriodicalIF":4.2,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146115099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prosaposin in CNS health and disease, metabolic stress and exercise adaptation.","authors":"Hash Brown Taha, Shirley Zhu, Eric Wang","doi":"10.1007/s00109-026-02643-3","DOIUrl":"10.1007/s00109-026-02643-3","url":null,"abstract":"<p><p>Prosaposin (PSAP), a highly conserved lysosomal protein and precursor of saposins A-D, has emerged as a key regulator of cellular and central nervous system (CNS) homeostasis. Disrupted PSAP trafficking may lead to amyloid protein aggregation with implications for neurodegenerative diseases. In Alzheimer's disease (AD) and Parkinson's disease (PD), PSAP shows altered expression patterns and pathological co-localization with amyloid aggregates. PSAP variants are linked to multiple neurodegenerative diseases, including synucleinopathies, Gaucher's disease, and metachromatic leukodystrophy. Its levels are elevated in blood and cerebrospinal fluid in some individuals with AD or PD and are upregulated by stress conditions such as nerve injury and cold adaptation, but not by exercise. Prosaptides, short peptides derived from PSAP, show protective effects in models of oxidative stress, CNS injury, and metabolic disorders. Pharmacological stabilization of PSAP interactions with progranulin has shown promise in neurodegenerative disease models. These findings suggest PSAP plays an important role in maintaining brain health and may hold therapeutic potential. Here, we provide a comprehensive overview of PSAP's role in CNS health and disease, metabolic stress, and exercise adaptation.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":"38"},"PeriodicalIF":4.2,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12864279/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146109591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bridging gaps in mitochondrial disease diagnosis: the role of advanced biomarker discovery.","authors":"Tendai Makwikwi, Maryke Schoonen, Izelle Smuts, Francois H van der Westhuizen","doi":"10.1007/s00109-026-02646-0","DOIUrl":"10.1007/s00109-026-02646-0","url":null,"abstract":"","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":"36"},"PeriodicalIF":4.2,"publicationDate":"2026-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12860861/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146095325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DAPL1 is activated by Np63 and GRα and regulates lipid metabolism.","authors":"Heung-Seok Bae, Yong-In Kim, DongWook Kim, Ki-Hoan Nam, KyungSook Han, SunJo Kim, SungWon Kwon, Je-Yoel Cho","doi":"10.1007/s00109-025-02636-8","DOIUrl":"10.1007/s00109-025-02636-8","url":null,"abstract":"<p><p>Non-small cell lung cancer (NSCLC) accounts for about 80% of all lung cancer occurrences and is divided into largely Adenocarcinoma (LUAD), Squamous cell carcinoma (LUSC), and Large cell carcinoma. In this study, using RNA-seq data between cancer tissues and adjacent normal tissues of 5 LUAD and 4 LUSC patients, we found that a Death associated protein like 1 (DAPL1) was highly expressed in squamous cell carcinoma but not in adenocarcinoma. Through the RNA-seq analysis, we found that lipid metabolic pathway genes Fdft1, Pcyt1a, and Sptlc1 correlate well with DAPL1 level changes in LUSC. We also found that Dapl1 was activated by Np63 and GRα monomer transcription factors. We generated a DAPL1 knockout mouse, which shows body weight and hair color changes, implying the role of DAPL1 in lipid metabolism. Our data show that Np63, GRα transcription factors activate DAPL1, and it is predicted to contribute to cellular acidification by regulating lipid metabolism based on mRNA-seq data and DAPL1 KO mice. KEY MESSAGES: This study uses RNA-seq data between cancer tissues and adjacent normal tissues of 5LUAD and 4LUSC patients. We found that a Death associated protein like 1 (DAPL1) was highly expressed in squamous cell carcinoma but not in adenocarcinoma. We also found that Dapl1 was activated by Np63 and GRα monomer transcription factors. The RNA-seq analysis found that lipid metabolic pathway genes Fdft1, Pcyt1a, and Sptlc1 correlate well with DAPL1 level changes in LUSC. We generated a DAPL1 knockout mice. DAPL1 KO mice were bred at two institutions (KRIBB for phonotypes, and SNU for functions). Interestingly, in KRIBB, DAPL1 KO body weight was lower than WT, and in SNU, DAPL1 KO body weight was higher than WT. In the investigation of mouse chow from the two institutions, differences in choline were noted. When chow with differences only in choline was produced and applied to new DAPL1 KO mice, the same results were obtained. Through RNA-seq data and body weight changes in DAPL1 KO mice, we report that DAPL1 regulates cholesterol, PC, and SM through changes in mRNA of Fdft1, Pcyt1a, and Sptlc1. Our data show that Np63, GRα monomer transcription factors activate DAPL1, and it is predicted to regulate lipid metabolism based on mRNA-seq data and DAPL1 KO mice.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":"37"},"PeriodicalIF":4.2,"publicationDate":"2026-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12860865/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146095390","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Temozolomide increases the generation of cell heterogeneity in ERK activity in glioma cells.","authors":"Karine Rech Begnini, Julia Caroline Marcolin, Luiza Cherobini Pereira, Letícia Cunha Pereira de Souza, Frederico Kraemer-Mattos, Daphne Tórgo, Carolina Machemer, Georgia da Silva Goulart, Andrew Oliveira Silva, Jephesson Alex Floriano Dos Santos, Guido Lenz","doi":"10.1007/s00109-026-02644-2","DOIUrl":"10.1007/s00109-026-02644-2","url":null,"abstract":"<p><p>ERK activity governs diverse cellular responses and has significant implications in cancer biology and treatment. Cellular heterogeneity is a major feature of cancer and a barrier for therapy success, allowing cancer cells to adapt and survive in challenging environments. Here, we used a genetic live-cell reporter to explore the heterogeneity of ERK signaling activity within cellular populations and colonies of glioblastoma (GB) cells. GB cells showed a wide spectrum of ERK activation levels in basal culture conditions and throughout state transitions. Treatment with the chemotherapeutic agent temozolomide increased the phenotypic heterogeneity in ERK activity within cells even in clonal populations. Using the MEK inhibitor trametinib in combination with temozolomide to homogenize ERK activity reduced cell fitness in colonies and decreased fractional killing in GB clonal cells. Our study contributes to the growing understanding of the complexity in ERK activity and dynamics, pointing out the consequences of cell-to-cell ERK phenotypic variability in fitness and therapy survival. The complexity of ERK signaling phenotypes in the context of chemotherapy treatment is shown, offering valuable insights about the intricacies of ERK signaling heterogeneity and chemotherapy treatment. KEY MESSAGES: Heterogeneity in ERK activity in live GBM cells is high in basal culture conditions. Temozolomide alters ERK activity in GBM cells and generates phenotypic heterogeneity. Clonal populations behave heterogeneously in ERK activity, and this heterogeneity impacts fitness. Targeting the generation of ERK heterogeneity reduces fitness and fractional killing in GBM colonies.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":"35"},"PeriodicalIF":4.2,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12855392/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146088837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alcohol induces sorafenib resistance in hepatocellular carcinoma: A translational study.","authors":"Anoïsia Courtois, Constance Marié, Gregory Fouquet, Momar Diouf, Damien Esparteiro, Gérard Ducournau, Léa Marticho, Mickaël Naassila, Eric Nguyen-Khac, Ingrid Marcq","doi":"10.1007/s00109-026-02645-1","DOIUrl":"10.1007/s00109-026-02645-1","url":null,"abstract":"<p><p>Alcohol is a major cause of hepatocellular carcinoma (HCC), accounting for 30% of cases worldwide. Sorafenib, a tyrosine kinase inhibitor (TKI), was the standard first-line treatment for advanced HCC until 2021, but sorafenib resistance is common. We explored the impact of chronic alcohol exposure (CAE) on sorafenib response and sought to identify associated resistance mechanisms. Huh-7 HCC cells were chronically exposed to alcohol for 6 months. Sorafenib resistance was assessed by measuring cell viability (IC50) and by evaluating the protein expression of signaling pathways involved in resistance using immunoblotting. RNA sequencing was performed to identify mechanisms of resistance. Sorafenib response was assessed using the RECIST 1.1 criteria in HCC patients. A retrospective study of 86 HCC patients from the CHIEF cohort (alcohol-related vs. non-alcohol-related etiologies) evaluated overall survival (OS) and progression-free survival (PFS) using the log-rank test. CAE significantly decreased cell sensitivity to sorafenib (p = 0.006), indicating increased resistance. The ERK pathway was involved. RNA sequencing of our cells identified a total of 80 differentially expressed genes associated with drug resistance and aggressiveness. Clinically, alcohol-related HCC patients were less responsive to sorafenib (35% responders vs. 65%, p = 0.014) and had significantly different OS (p = 0.0234). Median OS was 10 months (95% CI = [6.1, 15.7]) for alcohol-related HCC and 12.1 months (95% CI = [7.7, 64.9]) for other etiologies. PFS was lower in the alcohol group (5.72 months (95% CI = [4.63, 12.8]) vs. 9.66 months (95% CI = [4.40, 39.9], p = 0.0298). Sorafenib resistance due to chronic alcohol consumption is consistent in both in vitro models and clinical settings. KEY MESSAGES: Chronic alcohol exposure reduces the effectiveness of sorafenib in hepatocellular carcinoma (HCC), as demonstrated in both in vitro and clinical settings. In vitro, alcohol-exposed HCC cells showed increased sorafenib resistance, associated with activation of the ERK signaling pathway and differential expression of 80 genes linked to drug resistance and tumor aggressiveness. Clinically, patients with alcohol-related HCC had poorer responses to sorafenib and shorter overall and progression-free survival compared to patients with non-alcohol-related HCC. These findings suggest that alcohol-related HCC may require alternative or personalized therapeutic strategies beyond standard TKI treatments.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":"34"},"PeriodicalIF":4.2,"publicationDate":"2026-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12831666/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146044521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}