Xinrui Jin, Sherlot Juan Song, Jimmy Che-To Lai, Grace Lai-Hung Wong, Alice Pik-Shan Kong, Nana Peng, Xiang Xiao, Vincent Wai-Sun Wong, Terry Cheuk-Fung Yip
Received July 31, 2025 Accepted November 27, 2025 Published online December 1, 2025
Background/Aims
Previous studies suggest that hypothyroidism is associated with metabolic dysfunction-associated steatotic liver disease (MASLD) and its histological severity, but clinical outcome data are largely lacking. We aimed to study the impact of hypothyroidism on liver-related events (LREs).
Methods
Patients with MASLD were identified from a territory-wide registry in Hong Kong during 2000-2024. Thyroid status was determined using diagnosis codes and thyroid function tests. The primary outcome, LRE, was defined as a composite of hepatic decompensation, hepatocellular carcinoma, liver transplantation, and liver-related death.
Results
A total of 20,478 patients with MASLD were included in the final analysis (mean age 56.4±13.2 years; 43.9% male). At baseline, 18,178 (88.8%) patients were euthyroid, 598 (2.9%) were hyperthyroid, and 1,702 (8.3%) were hypothyroid. Compared with euthyroid patients, both hyperthyroidism and overt hypothyroidism were associated with cirrhosis. At a median follow-up of 4.8 years, 179 patients developed LREs, and 26 died from liver disease. Compared with patients with normal serum thyroid-stimulating hormone (TSH) levels of 0.4-4 mIU/L, those with subclinical (4-10 mIU/L; adjusted time-dependent cause-specific hazard ratio [aCSHR] 2.49, 95% CI 1.51-4.13) and overt hypothyroidism (>10 mIU/L; aCSHR 4.91, 95% CI 1.56-15.47) had an increased risk of LREs. Time-dependent, but not baseline, TSH and thyroid status were associated with LRE risk.
Conclusions
Subclinical and overt hypothyroidism are associated with an increased risk of LREs in a dose-dependent manner. The association with time-dependent but not baseline thyroid status underscores the importance of thyroid monitoring and suggests that correction of hypothyroidism may mitigate LRE risk.
Won Suk Lee, Seonjeong Woo, Sung Hwan Lee, Gae Hoon Jo, Ilhwan Kim, Hyeyeong Kim, Chansik An, Sanghoon Jung, Gwangil Kim, Haeyoun Kang, Beodeul Kang, Jung Sun Kim, Ho Yeong Lim, Incheon Kang, Hannah Yang, So Jung Kong, Dahyeon Son, Dong Jun Shin, Woo Young Kwon, Da-Yeon Lee, Ju-Seog Lee, Junho Park, Youngsoo Kim, Sohyun Hwang, Chan Kim, Hong Jae Chon
Received July 17, 2025 Accepted October 26, 2025 Published online October 27, 2025
Background/Aims Hepatocellular carcinoma (HCC) exhibits substantial morphological and biological heterogeneity. Clinical and molecular relevance of the infiltrative subtype remains poorly defined in the context of cancer immunotherapy. We aimed to evaluate the prognostic impact and molecular features of infiltrative HCC in patients treated with first-line atezolizumab plus bevacizumab (Ate/Bev).
Methods We included 307 patients with advanced HCC treated with Ate/Bev and classified them into four gross morphological types based on imaging. Multi-omics profiling was conducted on tumor samples. Type IV infiltrative signature was derived and externally validated using five independent HCC cohorts, including IMbrave150.
Results Infiltrative morphology, encompassing pure and mixed forms, was present in 42.7% of advanced HCC and associated with advanced disease features and compromised liver function. Patients with type IV infiltrative HCC showed lowest objective response rate (14.6%) and worst progression-free (median, 2.8 months) and overall survival (median, 7.1 months). Infiltrative morphology remained an independent predictor of poor outcomes after multivariable adjustment for confounders, including intrahepatic tumor extent. Genomic profiling revealed enriched TP53 and ATM loss-of-function mutations in type IV infiltrative HCC. Transcriptomic and proteomic analyses identified consistent activation of tumor proliferation, epithelial-mesenchymal transition, TGF-β signaling, and immunosuppressive pathways in type IV infiltrative HCC. Type IV infiltrative signature was significantly associated with poor survival across external datasets and retained independent prognostic value.
Conclusions Infiltrative HCC is a clinically aggressive and molecularly distinct subtype of advanced HCC. Morphological classification and type IV infiltrative signatures may guide risk stratification and therapeutic decision-making in advanced HCC treated with immunotherapy.
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and remains a major cause of cancer-related mortality worldwide. Systemic therapies, including targeted therapies and immune checkpoint inhibitors (ICIs), have revolutionized the management of advanced HCC. Although the prognosis of patients with advanced HCC remains poor, significant progress has been made with recent advances in drug development, particularly with the introduction of effective treatments such as atezolizumab plus bevacizumab or durvalumab plus tremelimumab. Indeed, treatment response varies significantly among patients, highlighting the need for robust biomarkers. In addition, the development of molecular driver-targeted therapies remains an active research focus as most genetic alterations observed in HCC are currently undruggable. Meeting these goals will require additional efforts to obtain histological material in clinical trials, in order to enable robust translational research. This review explores the current landscape of biomarkers of response to systemic treatments in HCC, including molecular, immune-based markers as well as circulating tumor DNA and highlights potential paths of improvement.
Intermediate-stage hepatocellular carcinoma (HCC) encompasses a diverse patient population that requires individualized treatment strategies and a multidisciplinary approach. Recent advancements in systemic therapy have expanded the therapeutic options for intermediate-stage HCC, allowing for combination strategies such as systemic therapy with transarterial chemoembolization (TACE) and upfront systemic therapy for individuals deemed unsuitable for TACE. Additionally, the ongoing development of treatment modalities for intermediate-stage HCC has improved the potential for curative conversion and tumor downstaging. Nevertheless, consensus on the optimal management of intermediate-stage HCC remains limited. Thus, the primary aim of this study was to develop a set of consensus guidelines for the management of intermediate-stage HCC. To address this gap, the Taiwan Liver Cancer Association (TLCA) established a working group to develop a multidisciplinary strategy for managing intermediate-stage HCC. Here, we present eight consensus statements formulated by this expert panel, which outline criteria for TACE unsuitability, treatment recommendations based on TACE eligibility, and considerations for various modalities, including conventional TACE, drug-eluting bead TACE, and transarterial radioembolization, as well as the appropriate timing for initiating systemic therapy to enable curative conversion and downstaging. These statements provide specific, evidence-based recommendations for clinicians, addressing treatment pathways based on TACE eligibility and other key considerations for intermediate-stage HCC management. The development of this consensus guideline is intended to aid clinicians in selecting the most appropriate treatment pathway for intermediate-stage HCC, support personalized treatment planning, and ultimately enhance the feasibility of achieving curative conversion.
Through the implementation of hepatitis B vaccination and effective antiviral treatment over the past four decades, the hepatitis B surface antigen (HBsAg) seroprevalence of the vaccinated generation dramatically decline. The incidence of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) also decreases. However, the elimination of HBV is still a challenge to achieve. Novel HBV biomarkers, including quantitative HBsAg, hepatitis B virus core-related antigen and HBV RNA are promising in predicting clinical phases, risks of disease progression and HBV functional cure. Current antiviral therapies, nucleoside/nucleotide and pegylated alpha-interferon, effectively decrease HCC incidence in chronic hepatitis B (CHB) patients and minimize the recurrence of HCC in patients receiving curative therapy. Novel agents under development to achieve HBV cure include direct-acting antivirals that target various stages of the HBV lifecycle and host targeting agents that enhance HBV-specific immunity. The action plans for eliminating hepatitis B in the future are universal HBV screening, early and simplified treatment as well as precision lifelong management for CHB patients. This narrative review will summarize and discuss global strategies and initiatives aimed at eliminating HBV infection.
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Aspirin Use and Risk of HCC and Gastrointestinal Bleeding in Patients With HBV‐Related Cirrhosis: A Landmark Analysis Mi Na Kim, Geun U. Park, Seng Chan You, Jae Seung Lee, Hye Won Lee, Beom Kyung Kim, Seung Up Kim, Jun Yong Park, Do Young Kim, Sang Hoon Ahn Journal of Gastroenterology and Hepatology.2025; 40(11): 2750. CrossRef
Dong Wook Kim, Won Chang, So Yeon Kim, Young-Suk Lim, Jonggi Choi, Jungheum Cho, Jin-Wook Kim, Jai Young Cho, Sun Kyung Jeon, Yun Bin Lee, Eun Ju Cho, Su Jong Yu, Kyung-Suk Suh, Kwang-Woong Lee, Dong Ho Lee
Clin Mol Hepatol 2025;31(4):1285-1297. Published online June 13, 2025
Background/Aims Hepatocellular carcinoma (HCC) frequently recurs after curative treatment, posing challenges to long-term survival. Although contrast-enhanced multiphasic computed tomography (CECT) is commonly used for detecting recurrence, it is associated with risks such as radiation exposure and contrast agent reactions. This study aimed to compare the diagnostic performance of non-contrast magnetic resonance imaging (NC-MRI) with CECT for detecting recurrent HCC.
Methods In this prospective multicenter intra-individual head-to-head comparison trial (study identifier: NCT05690451, KCT0006395), participants who had undergone curative treatment for HCC and remained recurrence-free for over two years were enrolled. Each participant underwent three follow-up imaging sessions at 2–6-month intervals using both CECT and NC-MRI. The primary outcome was the detection accuracy of each modality, analyzed using the generalized estimating equation analysis. Secondary outcomes included sensitivity and specificity.
Results The study included 203 participants with a total of 528 paired imaging sessions, identifying recurrent HCC in 22 cases (10.8%). Among these, 21 cases involved intrahepatic recurrence with a median tumor size of 1.3 cm, and one case had aortocaval lymph node metastasis. NC-MRI achieved a detection accuracy of 96.6% (196/203), higher than CECT’s 91.6% (186/203) (P=0.006). NC-MRI also showed greater sensitivity (77.3% [17/22] vs. 36.4% [8/22]; P=0.012), while specificity was comparable between NC-MRI and CECT (98.9% [179/181] vs. 98.3% [178/181]; P=0.999).
Conclusions NC-MRI demonstrated higher sensitivity and accuracy compared to CECT in detecting recurrent HCC in patients who had been disease-free for over two years following curative treatment, indicating its potential as a preferred imaging modality for this purpose.
Moana Witte, Carlos Oltmanns, Jan Tauwaldt, Hagen Schmaus, Jasmin Mischke, Gordon Grabert, Mara Bretthauer, Lennart M. Roesner, Thomas Werfel, Katja Deterding, Benjamin Maasoumy, Heiner Wedemeyer, Tim Kacprowski, Anke R.M. Kraft, Markus Cornberg
Clin Mol Hepatol 2025;31(4):1269-1284. Published online June 4, 2025
Background/Aims Hepatitis C virus (HCV) infection remains a global health challenge, leading to chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC). Despite the high efficacy of direct-acting antiviral therapy in achieving sustained virologic response (SVR), concerns persist regarding long-term immune alterations and residual risks, particularly in cirrhotic patients.
Methods This study investigates 75 soluble immune mediator (SIM) profiles in 102 chronic HCV patients, stratified by cirrhosis status, at therapy initiation, end of treatment, and long-term follow-up (median 96 weeks). Findings were compared with 51 matched healthy controls and validated in an independent cohort of 47 cirrhotic patients, 17 of whom developed HCC.
Results We observed significant SIM alterations at baseline, with cirrhotic patients displaying a more profoundly dysregulated inflammatory milieu. Despite an overall decline in inflammatory markers following SVR, persistent alterations were evident, particularly in cirrhotic patients. Notably, those with liver stiffness exceeding 14 kPa exhibited sustained inflammatory dysregulation, correlating with liver elastography values. Key SIM such as interleukin (IL)-6, IL-8, urokinase plasminogen activator, and hepatocellular growth factor remained elevated and were associated with HCC development. Network analysis highlighted their roles in liver fibrosis, regeneration, and carcinogenesis.
Conclusions These findings underscore the importance of early antiviral intervention to prevent cirrhosis-related sequelae. Future studies should explore the mechanistic pathways linking chronic inflammation, fibrosis, and oncogenesis to identify predictive biomarkers and novel therapeutic targets. Addressing persistent immune alterations post-HCV clearance may improve long-term outcomes, particularly in patients with advanced liver disease.
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HBV Dominance Is Associated With a Distinct Inflammatory Milieu in HBV/HCV Coinfection Carlos Oltmanns, Moana Witte, Anika Wranke, Katja Deterding, Heiner Wedemeyer, Christine S. Falk, Anke R. M. Kraft, Steffen B. Wiegand, Markus Cornberg Journal of Viral Hepatitis.2025;[Epub] CrossRef
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Background/Aims Hepatocellular carcinoma (HCC) is a highly heterogeneous disease, and abnormal MET expression plays a crucial role in its progression. However, the specific pathogenic mechanisms of MET in HCC have yet to be fully elucidated. This study aimed to uncover the oncogenic mechanisms of MET in HCC and explore potential therapeutic implications.
Methods Transcriptomic data from the HTVi MET/β-catenin HCC model and GSEA results from TCGA LIHC cohorts were analyzed to identify key genes in HCC development. In vitro assays and in vivo models were used to investigate the role of TRIB3 in HCC progression. Immunofluorescence, co-IP, qRT-PCR, and WB revealed target genes regulated by TRIB3. An AAV8-shTRIB3 construct was developed and we assessed its therapeutic potential.
Results MET promoted HCC development both in vitro and in vivo by upregulating the oncogenic protein TRIB3. Mechanistically, MET transcriptionally activated TRIB3 via the ERK/SP1 axis. TRIB3 then recruited the E3 ubiquitin ligase COP1, which facilitated the ubiquitination and degradation of the tumor suppressor transcription factor FOXO1. TRIB3-mediated FOXO1 ubiquitination upregulated the expression of MET, CCND1 and TWIST1. In clinical HCC samples, TRIB3 expression was correlated with MET and FOXO1 levels. Liver-specific knockdown of TRIB3 by AAV8-shTRIB3 significantly inhibited MET-driven HCC development.
Conclusions Our results revealed that TRIB3 and COP1 act as key mediators in MET-driven HCC progression. Targeting the MET-TRIB3-FOXO1 regulatory axis may offer a promising therapeutic strategy to counteract oncogenic signaling and impede HCC advancement.
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Background/Aims Given the increase in prevalence of metabolic diseases, we investigated their long-term impacts on the outcomes of chronic hepatitis B (CHB) patients receiving nucleos(t)ide analogue (NA) treatment.
Methods We analyzed data from CHB patients for whom initiated NA treatment from 30 centers. We balanced patient characteristics with and without metabolic disease (diabetes, obesity, dyslipidemia, and hypertension) via propensity-score matching (PSM) to evaluate adverse outcomes.
Results The study included 4,500 patients. PSM yielded 909 pairs of patients with balanced characteristics. When stratified by the number of metabolic diseases, only patients with ≥2 metabolic diseases had an increased cumulative incidence of cirrhosis and overall death. However, when stratified by the presence of diabetes (regardless of the presence or number of other metabolic diseases), patients with diabetes (versus those without) had a significantly higher cumulative incidence of all outcomes: cirrhosis (P=0.009), hepatocellular carcinoma (HCC, P=0.023), and overall, liver-related, and non-liver-related death (P<0.001, P=0.026 and P<0.001, respectively). Having ≥2 metabolic diseases was associated with cirrhosis, overall death, and non-liver-related death but not HCC or liver-related death, while diabetes was significantly associated with a higher risk of all outcomes: cirrhosis (hazard ratio [HR]=3.75, P=0.004), HCC (HR=2.02, P=0.020), and overall, liver-related, and non-liver-related death (HR=2.53, P<0.001; HR=2.65, P=0.016; HR=2.38, P<0.001).
Conclusions Having two or more metabolic diseases was associated with a higher risk of cirrhosis, overall death, and non-liver-related death, but having diabetes as a single metabolic disease was significantly associated with all adverse outcomes including cirrhosis, HCC, and overall, liver-related, and non-liver-related death.
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Background/Aims Previously, we advocated the importance of classifying hepatocellular carcinoma (HCC) based on physiological functions. This study aims to classify HCC by focusing on liver-intrinsic metabolism and glycolytic pathway in cancer cells.
Methods Comprehensive RNA/DNA sequencing, immunohistochemistry, and radiological evaluations were performed on HCC tissues from the training cohort (n=136) and validated in 916 public samples. HCC was classified using hierarchical clustering and compared with previous molecular, histopathological, and hemodynamic classifications.
Results Liver-specific metabolism and glycolysis are mutually exclusive and were divided into two major subclasses: The “rich metabolism” subclass (60.3%) is characterized by enhanced bile acid and fatty acid metabolism, wellto-moderate differentiation, microtrabecular or pseudoglandular pattern, and homogeneous arterial-phase hyperenhancement (APHE), corresponding to Hoshida S3 with favorable prognosis. In IL6-JAK-STAT3-high (25.0%) conditions, upregulated ALB expression, enhanced gluconeogenesis and urea cycle activity, and an inflammatorymicroenvironment are observed. Conversely, the Wnt/β-catenin-high environment (19.9%) features elevated GLUL, APOB and CYP3A4 expression, frequent CTNNB1 (D32–S37) mutations, and an immune-desert/excluded phenotype. The “glycolysis” subclass (39.7%), characterized by histopathological dedifferentiation and downregulated liver-specific metabolism, encompasses subclasses with PI3K/mTOR (20.6%) and NOTCH/TGF-β (19.1%) signaling. These often exhibit TP53 mutations, macrotrabecular massive or compact patterns, inhomogeneous/rim-APHE, and high expression of hypoxia-inducible factors and glucose transporters, corresponding to Hoshida S1/2 with poor prognosis.
Conclusions The loss of liver-specific metabolism correlates with morphological dedifferentiation, indicating cellular dedifferentiation may exhibit both physiological and pathological duality. Key signaling pathways involved in the maturation process from fetal to adult liver and zonation program may play a critical role in defining HCC diversity.
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Background/Aims The identification of factors that lead to CD8+ T cell dysfunction within the tumor microenvironment (TME) holds great promise for the development of innovative immunotherapies. However, the mechanisms underlying the exhausted phenotype of CD8+ T cells infiltrating early-stage hepatocellular carcinoma (HCC) tumors remain unclear.
Methods Single-cell RNA sequencing was performed using a murine HCC model. Flow cytometry and additional experimental approaches were employed to investigate the mechanisms of CD8+ T cell exhaustion.
Results CD8+ T cells infiltrating early-stage HCC exhibited a functionally exhausted phenotype, which escalated with HCC progression. At early stages of HCC, the TME was characterized by significant iron accumulation. Moreover, tumor-infiltrating CD8+ T cells in murine HCC exhibited higher levels of intracellular ferrous iron compared to splenic CD8+ T. This excessive iron led to increased lipid peroxide levels and impaired the effector function of CD8+ T cells. Mechanistically, CD36 upregulated the iron uptake protein transferrin receptor 1 (TfR1) by mediating the activation of oxidized low-density lipoprotein (oxLDL)-p38-CEBPB axis. Depletion of CD36 in CD8+ T cells inhibited the upregulation of TfR1 and the increase of iron levels. Furthermore, constitutively activated nuclear factor erythroid 2-related factor 2 (NRF2) effectively suppressed lipid peroxidation, thereby preserving the effector functions of intratumoral CD8+ T cells and ultimately inhibiting tumor growth.
Conclusions Our findings reveal a previously unidentified mechanism mediated by CD36 that regulates the progressive dysfunction of CD8+ T cells in early HCC TME and provide a potential novel therapeutic approach to restore T cell function.
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Hepatocellular carcinoma (HCC) is a highly lethal cancer due to its aggressive nature and poor prognosis. Adenosine, a key metabolic regulator in the tumor microenvironment (TME), plays a crucial role in cancer progression. In this review, we first described adenosine triphosphate adenosine metabolism in the TME and summarized its effects on tumor growth, immune suppression, angiogenesis, and metastasis in HCC. Given the limited number of clinical studies on adenosine signaling in HCC, we conducted LASSO-Cox analysis using the TCGA-LIHC cohort to develop a prognostic risk model composed of eight adenosine signaling-related genes. This model stratified the patients into low- and high-risk groups, with Kaplan-Meier survival analysis revealing poorer overall survival in the high-risk group. Additionally, differential gene expression analysis between the two groups identified 24 enriched signaling pathways for further investigation. Immune infiltration and single cell RNA-seq analyses revealed a correlation between adenosine and immunosuppressive activity in the TME, with a particularly strong association observed in macrophages, dendritic cells, and monocytes. Finally, we provided an overview of the advancements of antagonists that target adenosine receptors’ progress in both preclinical research and clinical trials. In conclusion, this review aims to deepen our understanding of the biological role of adenosine and highlights emerging therapeutic strategies that may improve treatment outcomes for HCC.
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Background/Aims Hepatocellular carcinoma (HCC) exhibits high de novo recurrence rates post-resection. Current post-surgery recurrence prediction methods are limited, emphasizing the need for reliable biomarkers to assess recurrence risk. We aimed to develop methylation-based markers for classifying HCC patients and predicting their risk of de novo recurrence post-surgery.
Methods In this retrospective cohort study, we analyzed data from HCC patients who underwent surgical resection in Korea, excluding those with recurrence within one year post-surgery. Using the Infinium Methylation EPIC array on 140 samples in the discovery cohort, we classified patients into low- and high-risk groups based on methylation profiles. Distinctive markers were identified through random forest analysis. These markers were validated in the cancer genome atlas (n=217), Validation cohort 1 (n=63) and experimental Validation using a methylation-sensitive high-resolution melting (MS-HRM) assay in Validation cohort 1 and Validation cohort 2 (n=63).
Results The low-risk recurrence group (methylation group 1; MG1) showed a methylation average of 0.73 (95% confidence interval [CI] 0.69–0.77) with a 23.5% recurrence rate, while the high-risk group (MG2) had an average of 0.17 (95% CI 0.14–0.20) with a 44.1% recurrence rate (P<0.03). Validation confirmed the applicability of methylation markers across diverse populations, showing high accuracy in predicting the probability of HCC recurrence risk (area under the curve 96.8%). The MS-HRM assay confirmed its effectiveness in predicting de novo recurrence with 95.5% sensitivity, 89.7% specificity, and 92.2% accuracy.
Conclusions Methylation markers effectively classified HCC patients by de novo recurrence risk, enhancing prediction accuracy and potentially offering personalized management strategies.
Reply to correspondence on “Aberrant fragmentomic features of circulating cell-free mitochondrial DNA enable early detection and prognosis prediction of hepatocellular carcinoma” Hyuk Soo Eun Clinical and Molecular Hepatology.2025; 31(2): e215. CrossRef
Jin Seoub Kim, Hye Seon Kim, Kwon Yong Tak, Ji Won Han, Heechul Nam, Pil Soo Sung, Sung Won Lee, Jung Hyun Kwon, Si Hyun Bae, Jong Young Choi, Seung Kew Yoon, Jeong Won Jang
Clin Mol Hepatol 2025;31(2):509-524. Published online January 2, 2025
Background/Aims Hepatocellular carcinoma (HCC) exhibits significant sex disparities in incidence, yet its molecular mechanisms remain unclear. We explored the role of telomerase reverse transcriptase (TERT) genetic alterations and hepatitis B virus (HBV) integration, both known major contributors to HCC, in sex-specific risk for HBV-related HCC.
Methods We examined 310 HBV-related HCC tissues to investigate sex-specific TERT promoter (TERT-pro) mutations and HBV integration profiles, stratified by sex and age, and validated with single-cell RNA sequencing (scRNA-seq) data.
Results Tumors predominantly exhibited TERT-pro mutations (26.0% vs. 0%) and HBV-TERT integration (37.0% vs. 3.0%) compared to non-tumorous tissues. While TERT-pro mutations increased with age in both sexes, younger males (≤60 years) showed marked predominance compared to younger females. Males had significantly more HBV integrations at younger ages, while females initially had fewer integrations that gradually increased with age. Younger males' integrations showed significantly greater enrichment in the TERT locus compared to younger females, alongside a preference for promoters, PreS/S regions, and CpG islands. Overall, TERT genetic alterations were significantly sex-differential in younger individuals (75.3% in males vs. 23.1% in females) but not in older individuals (76.9% vs. 83.3%, respectively). These alterations were associated with increased TERT expression. The skewed TERT abnormalities in younger males were further corroborated by independent scRNA-seq data.
Conclusions Our findings highlight the critical role of TERT alterations and HBV integration patterns in the male predominance of HCC incidence among younger HBV carriers, offering insights for future exploration to optimize sex-specific patient care and HCC surveillance strategies.
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Transcriptional regulation of tumor suppressor gene RASSF1A by HBx Yanhong Kang, Wei Li, Junfeng Wei, Lin Yang, Yi Kang Molecular and Cellular Probes.2025; 82: 102034. CrossRef
Background/Aims Transmembrane 4 L six family member 1 (TM4SF1) is highly expressed and contributes to the progression of various malignancies. However, how it modulates hepatocellular carcinoma (HCC) progression and senescence remains to be elucidated.
Methods TM4SF1 expression in HCC samples was evaluated using immunohistochemistry and flow cytometry. Cellular senescence was assessed through SA-β-gal activity assays and Western blot analysis. TM4SF1-related protein interactions were investigated using immunoprecipitation-mass spectrometry, co-immunoprecipitation, bimolecular fluorescence complementation, and immunofluorescence. Tumor-infiltrating immune cells were analyzed by flow cytometry. The HCC mouse model was established via hydrodynamic tail vein injection.
Results TM4SF1 was highly expressed in human HCC samples and murine models. Knockdown of TM4SF1 suppressed HCC proliferation both in vitro and in vivo, inducing non-secretory senescence through upregulation of p16 and p21. TM4SF1 enhanced the interaction between AKT1 and PDPK1, thereby promoting AKT phosphorylation, which subsequently downregulated p16 and p21. Meanwhile, TM4SF1-mediated AKT phosphorylation enhanced PD-L1 expression while reducing major histocompatibility complex class I level on tumor cells, leading to impaired cytotoxic function of CD8+ T cells and an increased proportion of exhausted CD8+ T cells. In clinical HCC samples, elevated TM4SF1 expression was associated with resistance to anti-PD-1 immunotherapy. Targeting TM4SF1 via adeno-associated virus induced tumor senescence, reduced tumor burden and synergistically enhanced the efficacy of anti-PD-1 therapy.
Conclusions Our results revealed that TM4SF1 regulated tumor cell senescence and immune evasion through the AKT pathway, highlighting its potential as a therapeutic target in HCC, particularly in combination with first-line immunotherapy.
Citations
Citations to this article as recorded by
Regulation of cellular senescence in tumor progression and therapeutic targeting: mechanisms and pathways Bowei Liu, Zhigang Peng, Hao Zhang, Nan Zhang, Zaoqu Liu, Zhiwei Xia, Shaorong Huang, Peng Luo, Quan Cheng Molecular Cancer.2025;[Epub] CrossRef
TM4SF1 - A new immune target for treatment of hepatocellular carcinoma: Editorial on “Targeting TM4SF1 promotes tumor senescence enhancing CD8+ T cell cytotoxic function in hepatocellular carcinoma” Chen Rui Yuan, Terence Kin Wah Lee Clinical and Molecular Hepatology.2025; 31(2): 646. CrossRef
Targeting TM4SF1 to overcome immunotherapy resistance in hepatocellular carcinoma: Editorial on “Targeting TM4SF1 promotes tumor senescence enhancing CD8+ T cell cytotoxic function in hepatocellular carcinoma” Valerie Chew Clinical and Molecular Hepatology.2025; 31(2): 642. CrossRef
Correspondence to editorial on “Targeting TM4SF1 promotes tumor senescence enhancing CD8+ T cell cytotoxic function in hepatocellular carcinoma” Weifeng Zeng, Furong Liu, Yachong Liu, Zhanguo Zhang Clinical and Molecular Hepatology.2025; 31(2): e197. CrossRef
Tetraspan(in)-mediated immune regulation in hepatocellular carcinoma: Editorial on “Targeting TM4SF1 promotes tumor senescence enhancing CD8+ T cell cytotoxic function in hepatocellular carcinoma” Seo Hee Jin, Dong Joo Kim, Jung Weon Lee Clinical and Molecular Hepatology.2025; 31(2): 650. CrossRef
Differential Infiltration of T-Cell Populations in Tumor and Liver Tissues Predicts Recurrence-Free Survival in Surgically Resected Hepatocellular Carcinoma Eun Ji Jang, Ho Joong Choi, Young Kyoung You, Deok Hwa Seo, Mi Hyun Kwon, Keungmo Yang, Jaejun Lee, Jeong Won Jang, Seung Kew Yoon, Ji Won Han, Pil Soo Sung Cancers.2025; 17(9): 1548. CrossRef
Immunoregulatory mechanisms in the aging microenvironment: Targeting the senescence-associated secretory phenotype for cancer immunotherapy Haojun Wang, Yang Yu, Runze Li, Huiru Zhang, Zhe-sheng Chen, Changgang Sun, Jing Zhuang Acta Pharmaceutica Sinica B.2025; 15(9): 4476. CrossRef
Targeting tumor-associated macrophages to overcome immune checkpoint inhibitor resistance in hepatocellular carcinoma Fen Liu, Xianying Li, Yiming Zhang, Shan Ge, Zhan Shi, Qingbin Liu, Shulong Jiang Journal of Experimental & Clinical Cancer Research.2025;[Epub] CrossRef
Correspondence to editorial on “Aberrant fragmentomic features of circulating cell-free mitochondrial DNA enable early detection and prognosis prediction of hepatocellular carcinoma” Yang Liu, Fan Peng, Siyuan Wang, Jinliang Xing Clinical and Molecular Hepatology.2025; 31(2): e166. CrossRef
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