Elisa Pagliari, Alessia Anastasia, Floriana Bellandi, Manuela Garbellini, Jessica Ongaro, Michela Taiana, Giacomo P Comi, Linda Ottoboni, Julieth Andrea Sierra-Delgado, Shibi Likhite, Kathrin C Meyer, Monica Nizzardo, Stefania P Corti
{"title":"AAV9 gene therapy optimization for SMARD1/CMT2S: safety and long-term efficacy comparison of two vectors in a SMARD1 preclinical model.","authors":"Elisa Pagliari, Alessia Anastasia, Floriana Bellandi, Manuela Garbellini, Jessica Ongaro, Michela Taiana, Giacomo P Comi, Linda Ottoboni, Julieth Andrea Sierra-Delgado, Shibi Likhite, Kathrin C Meyer, Monica Nizzardo, Stefania P Corti","doi":"10.1186/s12929-025-01204-z","DOIUrl":"10.1186/s12929-025-01204-z","url":null,"abstract":"<p><strong>Background: </strong>Mutations in the Immunoglobulin Mu DNA Binding Protein 2 (IGHMBP2) gene cause Spinal Muscular Atrophy with Respiratory Distress type 1 (SMARD1), a rare, infantile, and fatal motor neuron disease, as well as the milder Charcot-Marie-Tooth disease type 2S (CMT2S). Gene therapy has emerged as a promising approach to correcting IGHMBP2 loss in SMARD1 models, but critical challenges remain.</p><p><strong>Methods: </strong>In this study, we compared the efficacy of two novel, optimized adeno-associated virus 9 (AAV9)-IGHMBP2 vectors, utilizing either the Chicken β-Actin (CBA) or a truncated form of the methyl-CpG-binding protein 2 (MeCP2) promoter (P546), in the SMARD1 murine model via intracerebroventricular delivery. Treated mice survival, histopathological and molecular profile were analyzed.</p><p><strong>Results: </strong>Corroborating previous findings, both constructs effectively rescued the pathological phenotype, significantly improving survival, body weight, and motor function while preserving motor neurons and neuromuscular junctions. Notably, histopathological and RNA sequencing analyses revealed, for the first time, inflammatory marker alterations in the SMARD1 spinal cord, which resolved following treatment. A comparative analysis of the two vectors demonstrated superior long-term efficacy of the P546-promoter construct.</p><p><strong>Conclusion: </strong>ICV gene therapy approach can effectively rescue SMARD1 pathological hallmarks, including astrogliosis and microgliosis. Moreover, P546-promoter construct is superior in terms of safety profile and long-term therapeutic efficacy.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"33 1","pages":"1"},"PeriodicalIF":12.1,"publicationDate":"2026-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12765291/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145900476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"High-CD14-expressing urothelial cancer cells foster a neutrophil-rich tumor microenvironment that increases the risk of radiation-promoted distant metastasis.","authors":"Yun Chiang, Yu-Chieh Tsai, Chung-Chieh Wang, Fu-Jen Hsueh, Chao-Yuan Huang, Chung-Hsin Chen, Yeong-Shiau Pu, Shih-Chieh Chueh, Xavier Cheng-Hong Tsai, Jason Chia-Hsien Cheng","doi":"10.1186/s12929-025-01201-2","DOIUrl":"10.1186/s12929-025-01201-2","url":null,"abstract":"<p><strong>Background: </strong>Radiation (RT)-promoted distant metastasis (DM) is an underrecognized complication that can compromise the therapeutic efficacy of local RT. This study aimed to identify tumor microenvironment (TME) traits that predispose to RT-promoted DM and provide mechanistic insights for potential therapeutic intervention.</p><p><strong>Methods: </strong>We performed NanoString analysis on tumor samples from urothelial cancer patients to compare the TME profiles of those with and without RT-promoted DM. To complement clinical findings, we conducted RNA sequencing (RNAseq) of murine bladder cancer cell lines, MB49 (with RT-promoted DM) and MBT2 (without), followed by in vivo ectopic tumor modeling, flow cytometry of immune cell infiltrates, and cytokine array profiling.</p><p><strong>Results: </strong>NanoString analysis revealed a significant enrichment of C-X-C motif receptor 2 (CXCR2)-expressing neutrophils in the TME of patients with RT-promoted DM. These tumors also exhibited nuclear factor kappa B (NFκB) activation and increased secretion of neutrophil-recruiting chemokines. RNAseq and cytokine profiling identified CD14 expression in tumor cells as a key upstream regulator of neutrophilic TME via NFκB signaling. The use of antagonists to block neutrophils and inhibit CD14 expression in cancer cells, which reduces the secretion of neutrophil-recruiting chemokines, effectively mitigated RT-promoted DM in both the MB49 and LLC mouse models.</p><p><strong>Conclusions: </strong>CD14 expression in tumor cells plays a pivotal role in shaping a neutrophil-enriched TME, which increases the susceptibility to RT-promoted DM. CD14 represents a potential predictive biomarker and therapeutic target for mitigating this adverse outcome.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"33 1","pages":"2"},"PeriodicalIF":12.1,"publicationDate":"2026-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12765301/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145900512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Post-translational modifications of immune checkpoints: molecular mechanisms, tumor microenvironment remodeling, and therapeutic implications.","authors":"Hung-Chia Hsieh, Lun-Ling Ling, Yi-Ching Wang","doi":"10.1186/s12929-025-01202-1","DOIUrl":"10.1186/s12929-025-01202-1","url":null,"abstract":"<p><p>Immune checkpoints play pivotal roles in regulating immune responses and maintaining tolerance. In cancer, these molecules are hijacked to suppress antitumor immunity, resulting in therapeutic resistance to immune checkpoint blockade (ICB). Recent advances have highlighted the critical role of post-translational modifications (PTMs), including phosphorylation, ubiquitination, glycosylation, palmitoylation, UFMylation, acetylation, SUMOylation, methylation, and ISGylation, in modulating checkpoint stability, trafficking, and function across diverse immune and tumor cell types. These dynamic PTMs reshape the tumor microenvironment (TME) by controlling immune cell function, antigen presentation, and inflammatory signaling. This review comprehensively outlines the mechanistic contributions of PTMs to immune checkpoint regulation, emphasizing how these PTMs orchestrate immune evasion and clinical outcomes. Special focus is given to PTMs of PD-L1, PD-1, TIM-3, TIGIT, CTLA-4, LAG-3, VISTA, BTLA, and SIRPα. We also discuss how targeting PTM-regulating enzymes or specific modification motifs offers a promising therapeutic strategy to overcome ICB resistance. Understanding the PTMs landscape provides critical insight into resistance mechanisms and unveils promising opportunities for rational combination therapies aimed at reprogramming the immunosuppressive TME and enhancing antitumor immunity.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"33 1","pages":"3"},"PeriodicalIF":12.1,"publicationDate":"2026-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12765318/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145900636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hyun-Jun Kim, Seon-Wook Kim, Jun-Hyeong Kim, Sang-Hoon Lee, Kyoung-Hwan Joo, Soo Young Lee, Hyunju Lee, Jung-Joon Min, Sang-Hee Cho, Da-Woon Jung, Darren R Williams
{"title":"CXCL5 neutralization mitigates cancer cachexia by disrupting CAF-cancer cell crosstalk.","authors":"Hyun-Jun Kim, Seon-Wook Kim, Jun-Hyeong Kim, Sang-Hoon Lee, Kyoung-Hwan Joo, Soo Young Lee, Hyunju Lee, Jung-Joon Min, Sang-Hee Cho, Da-Woon Jung, Darren R Williams","doi":"10.1186/s12929-025-01192-0","DOIUrl":"10.1186/s12929-025-01192-0","url":null,"abstract":"<p><strong>Background: </strong>Advanced metastasis produces cachexia, a complex skeletal muscle wasting syndrome that accounts for one-third of patient deaths. There is currently no approved drug therapy for cancer cachexia. Cancer-associated fibroblasts (CAF) within tumors have been hypothesized to contribute to cachexia, but the detailed mechanism(s) are unknown.</p><p><strong>Methods: </strong>Myotubes were treated with conditioned media (CM) from CAF or CAF activated by cancer cells. Upregulated chemokines in the cancer-activated CAF CM were identified by cytokine array. The effects of chemokine neutralization were investigated using in vitro myotube cultures and in vivo mouse models. The mechanism of action was characterized by in vivo RNA Seq and validated in human muscle cells. Immunostaining delineated the chemokine expression pattern in a patient tumor type highly associated with cachexia.</p><p><strong>Results: </strong>Cancer-activated CAF induced myotube atrophy. CXCL5 was as the major chemokine highly upregulated in the cancer-activated CAF. CXCL5 treatment alone induced myotube atrophy and inhibited myogenic ERK1/2 signaling, similar to cancer-activated CAF treatment. CXCL5 neutralization inhibited cachexia in mice co-injected with HCT 116 colon cancer cells and CAF. RNA Seq showed that CXCL5 neutralization upregulated hypertrophy-related PI3K-AKT-MyoG signaling and remodeled the muscle ECM. CXCL5 neutralization ameliorated muscle wasting induced by CXCL5 and IL-6 co-treatment, and also prevented atrophy in cancer-activated CAF CM-treated human myotubes. CAF were the major detectable source of CXCL5 in a patient tumor highly associated with cachexia.</p><p><strong>Conclusion: </strong>CAF contribute to cachexia via cancer cell crosstalk that upregulates CXCL5 secretion. CXCL5 neutralization offers a novel therapeutic approach to maintain muscle mass in cancer patients.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"32 1","pages":"107"},"PeriodicalIF":12.1,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12703897/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145756681","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Deidree V N Somanader-Livera, Chen Wei, Chao Wang, Yifang Li, Dorota Ferens, Ekaterina Salimova, Cordelia Selomulya, Mohammed Akhter Hossain, Chrishan S Samuel, Amlan Chakraborty
{"title":"Immune cell uptake of glycinated nanoparticles conjugated to anti-fibrotic peptides enables their prolonged activity and oral administration.","authors":"Deidree V N Somanader-Livera, Chen Wei, Chao Wang, Yifang Li, Dorota Ferens, Ekaterina Salimova, Cordelia Selomulya, Mohammed Akhter Hossain, Chrishan S Samuel, Amlan Chakraborty","doi":"10.1186/s12929-025-01198-8","DOIUrl":"10.1186/s12929-025-01198-8","url":null,"abstract":"<p><strong>Background: </strong>Fibrosis is a hallmark of various chronic diseases, for which there is no effective cure. Whilst the recombinant form of the human peptide hormone, relaxin (RLX), is being clinically evaluated for its cardioprotective including anti-fibrotic effects in heart failure patients, this is as an injectable which is invasive. This study therefore used biodegradable nanoparticles as a delivery platform to facilitate the prolonged activity and oral application of RLX and a related mimetic as therapeutics.</p><p><strong>Methods: </strong>RLX was conjugated to glycine-functionalised biodegradable superparamagnetic iron oxide nanoparticles (SPION-RLX), enabling therapeutic levels of RLX to be systemically or orally delivered to a murine model of cardiomyopathy. The oral (p.o) application of SPION-RLX was evaluated via daily drinking water (125 ng/5mls/day) from days 7-14 or via oral gavage every 72 h (25 ng/day) from days 14-42 post-injury. The longer-term anti-fibrotic effects of p.o administered SPION-RLX (25 ng/day) or SPION-B7-33 (25 ng/day), a single-chain RLX derivative and relaxin family peptide receptor 1 (RXFP1) agonist were compared to the frontline ACE inhibitor, perindopril (60 ng/day) from days 14-42 post-injury.</p><p><strong>Results: </strong>SPION-RLX was likely phagocytosed by surveiling RXFP1-expressing dendritic cells (DCs) and transported to the circulation and target site. This allowed for the systemic or oral administration of SPION-RLX to maintain its anti-fibrotic efficacy in mice with cardiomyopathy and restore organ dysfunction after 7 days of treatment. Single-cell transcriptomics provided insights into the phagosomal uptake of SPION-RLX which may have been mediated via scavenger receptors expressed by DCs. When orally administered every 72 h to mice with established cardiomyopathy over a 4 week period, SPION-RLX or SPION-B7-33 demonstrated greater anti-fibrotic efficacy than perindopril.</p><p><strong>Conclusion: </strong>The conjugation of RXFP1-binding peptides to glycine-functionalised biodegradable SPIONs allowed for their circumnavigation of the gut, and prolonged activity as orally administered therapies. These findings have significant ramifications for the oral administration of peptide therapies in general.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"32 1","pages":"104"},"PeriodicalIF":12.1,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12699924/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145743031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yang Dong, Cheuk-Lun Lee, Jianlin Li, Xiaofeng Liu, Qunxiong Zeng, Jiangming Zhong, Qingqing Zhang, Ting Wu, Vivian W Y Ng, Calvin K F Lee, Graham J Burton, Ernest H Y Ng, William S B Yeung, Ka-Wang Cheung, Philip C N Chiu
{"title":"Maternal causation of early-onset pre-eclampsia: excessive endometrial gland-derived apolipoprotein D induces placental ferroptosis and developmental abnormalities.","authors":"Yang Dong, Cheuk-Lun Lee, Jianlin Li, Xiaofeng Liu, Qunxiong Zeng, Jiangming Zhong, Qingqing Zhang, Ting Wu, Vivian W Y Ng, Calvin K F Lee, Graham J Burton, Ernest H Y Ng, William S B Yeung, Ka-Wang Cheung, Philip C N Chiu","doi":"10.1186/s12929-025-01199-7","DOIUrl":"10.1186/s12929-025-01199-7","url":null,"abstract":"<p><strong>Background: </strong>Early-onset pre-eclampsia (ePE) is a severe pregnancy complication characterized by dysregulated trophoblast functions and impaired placentation during early pregnancy, leading to substantial maternal and fetal morbidity. While circumstantial evidence indicates defective secretion from endometrial glands impairs placental development, direct evidence linking maternal glandular dysfunction to ePE pathogenesis remains elusive.</p><p><strong>Methods: </strong>We established endometrial glandular organoids from women with ePE and healthy pregnancies, analyzing their secretomes by iTRAQ-based proteomics, RNAseq, and spatial transcriptomics. Functional effects of organoid secretomes on trophoblasts were examined in vitro. An endometrial-specific apolipoprotein D (APOD) knock-in mouse model was studied in vivo. APOD levels in first-trimester serum samples from women who later developed ePE were compared to healthy pregnancies.</p><p><strong>Results: </strong>Secretomes from ePE derived endometrial organoids impeded spiral artery remodeling. Multiomic analyses revealed increased APOD production in both ePE organoids and decidual tissues. APOD overexpression disrupted trophoblast functions and endothelial vascular remodeling in vitro, and recapitulated ePE phenotypes in an APOD knock-in mouse model through PI3K/Akt-mediated placental ferroptosis and potential ER stress induction. Ferroptosis inhibition with Fer-1 rescued placental defects and PE symptoms in APOD knock-in mice. Elevated APOD levels in first-trimester serum samples from women who later developed ePE suggest its potential as an early biomarker.</p><p><strong>Conclusion: </strong>This study provides the first direct evidence linking dysregulated endometrial gland function to defective placentation and ePE. APOD was identified as a crucial endometrial gland-secreted factor contributing to ePE, suggesting its potential as an early biomarker and therapeutic target.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"32 1","pages":"103"},"PeriodicalIF":12.1,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12690863/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145714609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Screening strategy to identify Cas9 variants with higher HDR activity based on diphtheria toxin.","authors":"Daisuke Matsumoto, Komari Kubota, Yu Sato, Tomoko Kato-Inui, Kiyomi Nigorikawa, Yuichiro Miyaoka, Wataru Nomura","doi":"10.1186/s12929-025-01197-9","DOIUrl":"10.1186/s12929-025-01197-9","url":null,"abstract":"<p><strong>Background: </strong>In gene therapy via genome editing, it is essential to precisely repair disease-associated gene sequences without introducing random mutations. However, achieving highly accurate genome editing remains challenging owing to the low efficiency of homology-directed repair (HDR)-mediated gene repair, which relies on template DNA. Therefore, if Cas9 mutants capable of enhancing HDR can be identified, they could enable more precise gene therapies.</p><p><strong>Method: </strong>In this research project, we developed a screening system that uses the acquisition of diphtheria toxin resistance as an indicator of HDR efficiency in human cells and EGFP disruption as an indicator of off-target effect.</p><p><strong>Results: </strong>By screening a library of SpCas9 variants with random mutations introduced into its nuclease domain, we identified a novel SpCas9 mutant with higher HDR efficiency than wild-type Cas9.</p><p><strong>Conclusion: </strong>We explored the possibility of obtaining Cas9 mutants with high HDR efficiency via this screening system.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"32 1","pages":"102"},"PeriodicalIF":12.1,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12673799/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145661353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hannah Cruz, Prarthna Shah, Nicholas Wohlgemuth, Robert Ketchum, Imad Nassif, Chien-An A Hu
{"title":"Pyroptosis in ulcerative colitis: biomarkers and therapeutic targets.","authors":"Hannah Cruz, Prarthna Shah, Nicholas Wohlgemuth, Robert Ketchum, Imad Nassif, Chien-An A Hu","doi":"10.1186/s12929-025-01206-x","DOIUrl":"10.1186/s12929-025-01206-x","url":null,"abstract":"<p><strong>Background: </strong>Ulcerative colitis (UC) is one of the two major types of inflammatory bowel disease (IBD), characterized by inflammation of the colon and rectum. The colorectal epithelium, which covers the mucosal surface, maintains homeostasis by supporting commensal microorganisms in the outer mucus layer. Most colorectal epithelial cells (CECs) are absorptive colonocytes distributed primarily in the upper portion of the crypts. These CECs constitute the front-line barrier that modulates mucosal immunity and facilitates the transfer of immune molecules into the lumen. In patients with UC, CECs undergo both apoptosis and pyroptosis. Apoptosis is a physiological, programmed, caspase-dependent, and tightly regulated form of cell death that eliminates aged and damaged cells. In contrast, pyroptosis is an inflammatory, caspase-dependent form of lytic cell death that occurs in response to harmful stressors and toxins. Pyroptosis in CECs involves a broad array of signaling and effector molecules, many of which serve as measurable biomarkers with diagnostic, prognostic, and therapeutic potential.</p><p><strong>Conclusions: </strong>Dysregulated colorectal microflora significantly contributes to activating the pyroptotic pathway, initiating an inflammasome- and gasdermin-dependent inflammatory cell death process in UC patients. This review discusses the triggers and pathways of pyroptosis in CECs, evaluates recently identified biomarkers, highlights their potential roles in pyroptosis and as therapeutic targets in managing UC, and candidate compounds that have been shown effective UC therapeutics.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"32 1","pages":"106"},"PeriodicalIF":12.1,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12673710/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145668107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The impact of single-nucleotide variants of hepatitis B virus and antiviral on liver cancer in gray zone patients.","authors":"Wei Teng, Ting-Tsung Chang, Chien-Wei Su, Jun-Hao Xu, Chiu-Chi Hsu, Yu-Cheng Chang, Wen-Chun Liu, Yu-Wei Chiou, Yu-Chuan Chang, Yuh-Jin Liang, Jaw-Ching Wu","doi":"10.1186/s12929-025-01195-x","DOIUrl":"10.1186/s12929-025-01195-x","url":null,"abstract":"<p><strong>Objectives: </strong>This study investigated the impact and related mechanisms of single-nucleotide variants (SNVs) in the HBV pre-S/S region on tumor development, and evaluated the role of antiviral therapy.</p><p><strong>Methods: </strong>A retrospective analysis was conducted in 104 patients of the gray zone. HCC-associated SNVs were analyzed in baseline samples.</p><p><strong>Results: </strong>HCC occurred in 15 patients (14.4%) during the median follow-up period of 10.4 years. Genotype B HBV-infected HCC patients had more T53C, A273G, and A529G SNVs and genotype C HBV-infected HCC patients had more T53C, G633A, and A3120G SNVs than HCC-free groups. Antiviral therapy reduced the risk of HCC in patients with HCC-associated SNVs in the gray zone both genotype B or C. Ectopic expression of replication-competent HBV plasmids in Huh7 cells expressing HCC-associated SNVs resulted in greater impairment of mitochondrial dynamics, increased production of reactive oxygen species (ROS), decreased mitochondrial membrane potential, lower ATP production, higher basal calcium levels, and reduced calcium buffering capacity compared to controls or wild-type HBV-expressing cells.</p><p><strong>Conclusions: </strong>CHB patients in the gray zone remain at risk for HCC owing to both wild-type and HCC-associated HBV SNVs, especially the latter, inducing mitochondrial and metabolic dysfunctions. Antiviral therapy reduces the risk of HCC development in these patients.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"32 1","pages":"101"},"PeriodicalIF":12.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12667080/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145648655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}