Search Results (4,080)

Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide and exhibits considerable biological heterogeneity in both molecular and clinical characteristics. The diverse molecular alterations and clinical manifestations of HCC indicate substantial heterogeneity across patient subgroups. This study aimed to identify novel therapeutic targets and predictive biomarkers associated with HCC using an integrative bioinformatics approach. High-throughput genomic datasets were obtained from the UCSC Xena browser to retrieve mRNA HTSeq-count data from the TCGA-HCC cohort. Gene co-expression network (GCN), protein–protein interaction network (PPIN), and enrichment analyses were performed to identify key dysregulated genes and their biological significance. Integrated network analyses identified three dysregulated hub genes, namely CXCR2, TLR2, and TLR4. Genomic alterations in these genes were further evaluated across tumor samples in the TCGA-HCC cohort. Kaplan–Meier (KM) survival analysis demonstrated that lower CXCR2 mRNA expression was significantly associated with poorer overall survival (OS) and recurrence-free survival (RFS). Furthermore, TIMER and UALCAN analyses revealed significant associations between CXCR2 expression and tumor purity, as well as immune cell infiltration levels, including T cells, macrophages, dendritic cells (DCs), and neutrophils. These findings suggest that CXCR2 is significantly associated with the immune microenvironment of HCC and represents a potential prognostic biomarker whose biological role warrants further mechanistic investigation. Full article

Background: Predicting recurrence after liver transplantation (LT) for hepatocellular carcinoma (HCC) remains important for post-transplant risk stratification and surveillance planning. The Milan criteria discriminate only moderately and some machine-learning re-analyses report overly optimistic results because of information leakage. Aim: The current study aimed to re-evaluate a previously published transplant cohort under a leakage-free survival-analysis framework and to benchmark post-transplant, explant-informed survival learners against the Milan criteria as a fixed pre-transplant reference. We hypothesised moderate rather than near-perfect discrimination, similar performance across learners of differing complexity, and better discrimination than the Milan criteria. Methods: This secondary analysis included 356 patients with HCC who underwent LT. The primary endpoint was recurrence-free survival, analysed from the observed event indicator and follow-up time rather than from a derived risk label. Seven survival learners were benchmarked with repeated nested cross-validation, using three repeats of a five-fold outer loop with a three-fold inner tuning loop. All data-dependent preprocessing, including robust multivariable outlier handling and imputation, was fitted within training folds only. Performance was assessed by the concordance indices of Harrell and Uno, the time-dependent area under the curve, the integrated Brier score, calibration, decision-curve analysis and descriptive competing-risk assessment. Results: Recurrence developed in 183 of the 356 patients over a median follow-up of 52 months. Discrimination was moderate rather than near-perfect and similar across learners; the random survival forest ranked highest and the Elastic-Net Cox model performed comparably. All learners showed higher descriptive concordance than the Milan criteria, and dependency-corrected comparisons supported higher concordance for the full-feature Cox model than for the Milan criteria, whereas the random survival forest and Cox did not differ materially. Out-of-fold calibration of the Elastic-Net Cox model at 36 months was acceptable, decision-curve analysis indicated positive net benefit across clinically relevant thresholds, and tumour size and alpha-fetoprotein were the leading contributors to prediction. Findings were stable in ablation and threshold-sensitivity analyses. Conclusions: Leakage-free survival modelling gave moderate but internally validated prediction of post-transplant recurrence and higher concordance than the Milan criteria in this cohort, supporting the stated hypotheses. Careful study design may matter more than architectural complexity in this setting, and leakage-free survival analysis is a practical standard for prognostic modelling in transplant oncology. Full article

Background: The sensitivity of ultrasound plus alpha-fetoprotein (AFP) for early-stage hepatocellular carcinoma (HCC) detection remains suboptimal, prompting interest in blood-based biomarkers as an alternative strategy. The ASAP [age, sex, AFP, PIVKA-II] score has promising performance, although validation in contemporary Western populations is needed. Methods: We conducted a case–control study in which the cases were patients with HCC and the controls had cirrhosis without HCC. AFP, PIVKA-II, LG2m, and GP73 were measured using the Abbott Alinity platform, and ASAP scores were calculated. Sensitivity and specificity for early-stage HCC (BCLC stage 0/A) were compared between ASAP and ultrasound plus AFP using McNemar’s chi-square test. Results: Among 294 patients (median age of 61 years, 67.7% men), 50.7% had HCC (69.1% BCLC 0/A), and 49.3% had cirrhosis. The performance of individual biomarkers for early-stage HCC was moderate to poor (AUROC: AFP 0.71, PIVKA-II 0.73, LG2m 0.51, and GP73 0.53). ASAP, at a cutoff of ≥0.526, demonstrated a sensitivity of 88.3% for early-stage HCC, with specificity of 54.5%. Sensitivity was higher in men and viremic HCV, whereas specificity was higher in younger individuals, women, and Child–Pugh A cirrhosis. In subgroup analysis (n = 178), ASAP had comparable sensitivity to ultrasound plus AFP (85.5% vs. 90.3%; p = 0.51) but lower specificity (53.4% vs. 93.1%; p < 0.001). Using the Youden-optimized cutoff (≥0.804) improved specificity to 83.4% while maintaining a sensitivity of 68.0% for early-stage HCC. Conclusions: ASAP demonstrated high sensitivity for early-stage HCC detection but low specificity. These findings suggest a need for optimized cutoffs prior to implementation in clinical practice. Full article

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is frequently diagnosed at advanced stages, thereby limiting curative treatment options. Although interventions with curative intent, such as liver resection and ablation, are available, recurrence rates exceed 70%. Recent developments in HCC management have shifted the focus from conventional surgery and targeted therapies to immunotherapy. This review synthesizes current evidence on immunotherapy for curative purposes in HCC, including both neoadjuvant and adjuvant strategies. It evaluates completed and ongoing clinical trials of immune checkpoint inhibitors (ICIs), administered as monotherapy or in combination with anti-angiogenic agents or dual-checkpoint blockade. ICIs may transform the initial treatment paradigm for advanced HCC, although their applications remain in the investigational stage. Preliminary results from the IMbrave050 trial suggested that adjuvant immunotherapy following radical liver resection improves recurrence-free survival (RFS) in high-risk patients. However, the initially promising outcomes of the combination of atezolizumab and bevacizumab compared with active surveillance were not sustained in the median follow-up, and long-term survival results are awaited. Although several studies have demonstrated encouraging preliminary results, a clear survival benefit has not yet been established. Further studies are necessary to establish definitive conclusions. Immunotherapy has a pathophysiological basis and preliminary evidence to redefine HCC management across disease stages; its integration into pre- and post-operative strategies may increase resectability, reduce recurrence, and improve survival. Ongoing trials are expected to clarify its exact role. Full article

Background/Objectives: To investigate early treatment outcomes, including tumor response, predictors of response, and safety of nivolumab plus ipilimumab (Nivo/Ipi) therapy for unresectable hepatocellular carcinoma (uHCC) in a multicenter setting. Methods: We conducted a retrospective analysis of 64 Japanese patients with uHCC who received Nivo/Ipi therapy at participating centers between July 2025 and April 2026. Treatment efficacy was assessed according to RECIST version 1.1, and adverse events (AEs) were evaluated using CTCAE version 5.0. Results: Among the 64 patients, 28 received first-line therapy, and 36 received later-line therapy. The median observation period was 5.4 months. The overall response rate (ORR) was significantly higher in the first-line group (60.7%) than in the later-line group (30.6%) (p = 0.016). ORRs according to CRAFITY score were 25.0% for score 0, 55.6% for score 1, and 53.8% for score 2. The ORR in patients with CRAFITY scores ≥ 1 was significantly higher than in patients with a CRAFITY score of 0 (55.0% vs. 25.0%; p = 0.022). Multivariable analysis of pretreatment variables predicting response revealed first-line treatment (OR 3.83, 95% CI 1.270–11.558; p = 0.017) and a CRAFITY score ≥ 1 (OR 4.02, 95% CI 1.232–13.106; p = 0.021) as significant independent factors. Immune-mediated AEs occurred in 70.3% of patients overall and were grade ≥ 3 in 35.9%. Conclusions: Nivo/Ipi yielded a favorable response when used as first-line therapy. The baseline CRAFITY score may be a useful predictor of response to Nivo/Ipi therapy. Full article

The liver is an immunologically distinctive organ. Portal blood continuously delivers gut-derived antigens and microbial products, requiring hepatic immunity to balance surveillance with restraint. In hepatocellular carcinoma (HCC), this physiology is commonly overlaid by chronic injury, inflammation, and fibrosis, so the background liver forms part of the disease context in which the tumor microenvironment (TME) develops. This review synthesizes how cellular architecture, tumor-intrinsic programs, and structural, metabolic, and microbial conditions interact to shape immune evasion and heterogeneity. HCC provides the principal evidence base, with intrahepatic cholangiocarcinoma (iCCA) used as a structured, biologically distinct comparator. We organize therapies by the microenvironmental barriers they are intended to modify and distinguish established clinical efficacy from evidence that the proposed mechanisms mediate treatment benefit. Single-cell and spatial studies have resolved cellular states and spatial arrangements, including onco-fetal endothelial–myeloid neighborhoods and a macrophage–fibroblast boundary band separating lymphocyte-rich stroma from malignant tissue. These patterns operate within fibrotic and metabolically altered tissue and vary by etiology, spatial context, and tumor type. Vascular endothelial growth factor blockade with immune checkpoint inhibition and dual checkpoint blockade are established first-line options in advanced HCC. Chemo-immunotherapy is established in biliary tract cancer, and IDH1 inhibition has established efficacy in IDH1-mutant cholangiocarcinoma. Myeloid- and stroma-directed strategies, natural-product approaches, and engineered-cell therapies remain preclinical or early clinical. None of the pivotal trials tested whether the proposed microenvironmental mechanism mediated treatment benefit. The liver TME informs treatment selection without yet determining it. Full article

A coordinated extracellular matrix (ECM) and cytoskeletal remodeling are critical drivers of hepatocellular carcinoma (HCC) progression, yet the upstream post-transcriptional mechanisms regulating these processes in spontaneous canine HCC remain poorly defined. Previously, we reported significantly downregulated miRNAs and enriched pathways from differentially expressed genes (DEGs) in canine HCC tissues. In the present study, we investigated putative post-transcriptional target interactions between the prioritized miRNAs and enriched ECM–cytoskeleton pathway-associated genes (n = 34). Integrative bioinformatic analysis prioritized ACTG1 and SDC1 as the key putative targets of cfa-miR-10a based on their concordant prediction by four target-prediction algorithms, high transcript abundance, and inverse correlations with cfa-miR-10a-5p. RNAhybrid and miRanda analyses supported favorable predicted interactions between cfa-miR-10a and the 3′UTRs of both transcripts, with RNAhybrid minimum free energy values ≤ −20 kcal/mol and miRanda scores ≥ 140. In the matched canine transcriptomic subset, cfa-miR-10a and its predicted targets showed inverse expression trends. Cross-species analysis using TCGA-LIHC datasets further demonstrated concordant dysregulation of ACTG1, SDC1 and hsa-miR-10a-5p in human HCC, despite their weak or non-concordant correlation with hsa-miR-10a-5p. Collectively, these exploratory findings identify a candidate cfa-miR-10a–ACTG1/SDC1 network associated with coordinated ECM and cytoskeletal transcriptomic alterations in canine HCC. While cross-species analysis supports the conservation of target gene dysregulation, the divergent miRNA-mRNA correlation patterns highlight potential species-specific post-transcriptional co-expression landscapes that warrant future functional validation. Full article

(1) Background: The Hepatitis B virus (HBV) is characterized by extensive genetic diversity, including low-frequency variants that contribute to disease progression. We aimed to characterize low-frequency variants and evaluate their potential clinical impact. (2) Methods: We utilized 104 HBV near-full-length sequences generated using next-generation sequencing (NGS) from people living with HIV (PLHIV). We used an in-house bioinformatics suite (HBVgenomeR v5.9.7) to filter for low-frequency variants (5–50%), which were compared to escape and drug resistance mutations (DRMs) and hepatocellular carcinoma (HCC)-associated mutations reported at the consensus level. Unclassified variants were characterized by HBV open reading frames (ORFs) to determine mutation frequency per genomic region. (3) Results: A total of six escape mutations were detected in 8/104 (7.7%) sequences, with _surfaceN131T being the most prevalent (5/8). We also observed six DRMs in 30/104 (28.8%), with _rtV173L being the most prevalent (21/30). Truncation mutations were also observed with _rtA181T/_sW172* and _rtM204I/_sW196L being the most prevalent. A total of 8/104 (7.7%) sequences had four variants associated with HCC. The _xP46S was the highest observed HCC-associated mutation at 5/8. We report 1152 unique uncharacterized variants across all ORFs, and these were found in 94/104 (90.4%) sequences. The RNaseH domain had the highest burden (330/1152, 28.6%). (4) Conclusions: Deep sequencing results identified clinically significant mutations, including those below the 20% detection limit of traditional sequencing, that would go unreported. This highlights the possible underreporting of mutational burden in people living with HBV/HIV, indicating the importance of deep sequencing to aid in HBV/HIV understanding and management. Full article

Background/Objectives: Advanced-stage hepatocellular carcinoma is characterized by a very poor prognosis; thus, highly effective medication is still needed. Often overexpressed heat shock protein 90 is a promising target due to its pivotal role in carcinogenesis. Methods: Antiproliferative effects of 246TMP-3SF5 on HepG2 and HuH-7 cells were assessed by crystal violet staining. Apoptosis was evaluated via subG1 peak, caspase-3 activity and PARP cleavage, and ferroptosis via ROS, glutathione and malondialdehyde levels. Migration was assessed by scratch assay, and in ovo models were used to study angiogenesis and drug effects on microtumors. CAM vascular networks were quantified by semi-automatic segmentation, morphometric and box-counting fractal analysis. Molecular docking and molecular dynamics simulation of heat shock protein 90 were carried out using Autodock Vina and Gromacs respectively. Results: Profound dose- and time-dependent antiproliferative effects of 246TMP-3SF5 against HCC cell lines were observed, revealing low micromolecular IC₅₀ values and selectivity for carcinoma cells with selectivity indices > 1. A significant increase in the sub-G1 peak, key effector caspase-3 activity, as well as cleavage of PARP strongly suggested apoptosis playing a crucial role in the antiproliferative effects. Additionally, HuH-7 cells revealed an elevation of reactive oxygen species and both cell lines showed significant glutathione depletion concomitant with an increase in malondialdehyde concentration upon treatment. The observed effect could be partially reversed by applying ferrostatin-1, suggesting ferroptosis as an additional relevant mode of action. Changes in the cell cycle as well as impaired tumor cell migration were observed. Upon treatment, angiogenesis was impaired and mass of microtumors was significantly reduced. Quantitative CAM analysis showed that vascularized area fraction increased in controls but decreased under both 17-AAG and 246TMP-3SF5. Likewise global mean vessel width decreased relative to controls, while box-counting dimension was reduced under 246TMP-3SF5. Molecular docking and molecular dynamics simulation analysis predicts 246TMP-3SF5 to be binding in catalytic site of heat shock protein 90. Conclusions: 246TMP-3SF5 is a promising novel inhibitor meriting further research as a potential treatment against hepatocellular carcinoma. Full article

TCF3 fusion partner (TFPT) remains insufficiently characterized in hepatocellular carcinoma (HCC), particularly in relation to tumor growth and cellular features linked to lipid peroxidation defense. We integrated public transcriptomic and clinical datasets and established stable TFPT-knockdown and TFPT-overexpression models in MHCC97-H and Huh-7 cells. TFPT expression was higher in HCC tissues and selected HCC cell lines. In TCGA-LIHC, higher TFPT expression was associated with shorter overall survival after multivariable adjustment (HR, 1.37; 95% CI, 1.06–1.77), although this association was not reproduced in GSE14520. TFPT-high tumors were enriched for E2F Targets, MYC Targets, G2/M Checkpoint, and metabolic and cellular-stress-related programs. Internally constructed descriptive scores related to lipid peroxidation defense were higher in TFPT-high tumors but showed limited external reproducibility. In vitro, shTFPT cells showed lower CCK-8 signals, colony formation, monolayer closure, GSH levels, total glutathione peroxidase activity, and relative GPX4, SLC7A11, and FSP1 protein abundance, together with higher Fe²⁺ and MDA levels and higher BODIPY-C11 green-to-red fluorescence ratios; oeTFPT cells showed opposite patterns. These findings support an association between TFPT abundance and growth-related phenotypes and cellular features linked to lipid peroxidation defense in HCC, without establishing direct molecular regulation, ferroptotic cell death, causality, or independently validated prognostic utility. Full article

Background: Hepatocellular carcinoma (HCC) remains challenging to treat because of the limited therapeutic efficacy and insufficient selectivity of conventional therapies. To overcome these limitations, multifunctional nanoplatforms integrating biomimetic strategies and combination therapy have attracted increasing attention. Single-modality therapies are often limited by insufficient therapeutic efficacy and restricted mechanisms of action, highlighting the need for biomimetic nanoplatforms that integrate combination therapeutic strategies for enhanced antitumor performance. Methods: Herein, a biomimetic strategy-based nanoplatform (DI-ZM) was constructed via a combination of ZIF-8 biomineralization, physical adsorption of dihydroartemisinin (DHA) and indocyanine green (ICG), followed by HepG2 cell membrane coating to achieve homologous interaction. This design enables integrated chemotherapy, photothermal therapy (PTT), and photodynamic therapy (PDT) within a single system. Results: The resulting DI-ZM nanoparticles exhibited a hydrodynamic diameter of approximately ~200 nm with good colloidal stability and high drug-loading capacity. Under 808 nm laser irradiation, DI-ZM achieved a temperature elevation to ~66 °C within 5 min, together with efficient ROS generation. Compared with uncoated nanoparticles, the biomimetic membrane coating significantly enhanced cellular uptake and homologous targeting ability, as confirmed by CLSM and flow cytometry analysis. Benefiting from the biomimetic membrane coating, DI-ZM further exhibited improved homologous targeting and cellular uptake, which contributed to enhanced intracellular ROS generation. This was accompanied by significant mitochondrial membrane depolarization and apoptosis rates exceeding 80% in HepG2 cells under laser irradiation, ultimately resulting in markedly enhanced cytotoxicity. In addition, the biomimetic membrane coating also enabled efficient penetration of DI-ZM into multicellular tumor spheroids, indicating its improved tumor-penetration capability. In vivo antitumor studies further revealed effective tumor suppression with a tumor inhibition rate of approximately 97%, along with acceptable systemic tolerance in HepG2 tumor-bearing mice. Conclusion: The biomimetic membrane-coated ZIF-8 nanoplatform integrating chemotherapy with ICG-mediated phototherapy (photothermal and photodynamic therapy) provides an effective strategy for the combination therapy against HCC. Full article

Background: Hepatocellular carcinoma (HCC) remains a major clinical challenge due to its pronounced molecular heterogeneity and frequent resistance to conventional therapies. A key driver of therapeutic failure is the overexpression of the anti-apoptotic proteins myeloid cell leukemia-1 (Mcl-1) and B-cell lymphoma-extra large (Bcl-XL), which collectively maintain mitochondrial integrity and promote tumor cell survival. Methods: In this study, we evaluated a rational combination strategy targeting these complementary survival pathways using the histone deacetylase inhibitor panobinostat and the DNA-damaging agent bleomycin in HepG2 cells, a p53-functional HCC cell model. Results: In HepG2 cells, each agent alone produced only limited cytotoxicity, whereas their combination resulted in a marked and synergistic induction of apoptosis. This was shown by increased Annexin V positivity, mitochondrial outer membrane permeabilization (MOMP), and activation of caspases-8, -9, and -3 as well as cleavage of poly(ADP-ribose) polymerase (PARP). Mechanistically, panobinostat reduced Bcl-XL expression and primed mitochondria for apoptosis but simultaneously triggered compensatory upregulation of Mcl-1, representing an adaptive resistance response within this experimental system. Bleomycin effectively counteracted this escape mechanism by suppressing Mcl-1 induction, thereby lowering the apoptotic threshold and enabling mitochondrial permeabilization. In parallel, combined treatment potentiated caspase-8 cleavage, suggesting an additional caspase-8-associated apoptotic signal that amplified caspase-3/PARP execution. Pharmacological inhibition with zVAD-FMK confirmed that the observed cell death was predominantly caspase-dependent, supporting a coordinated engagement of both intrinsic and extrinsic apoptotic pathways. In summary, the combination of panobinostat and bleomycin overcomes anti-apoptotic defenses in HepG2 cells through synergistic and coordinated disruption of mitochondrial survival checkpoints and dual apoptosis pathway activation. Conclusions: By blocking a compensatory Mcl-1 escape response while simultaneously engaging extrinsic apoptosis signaling, this strategy produces potent synergistic cell death in this defined p53-functional HCC model and represents a promising mechanistic proof of concept that warrants further validation in additional molecularly diverse HCC models before broader translational conclusions can be drawn. Full article

Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection remain leading causes of cirrhosis and hepatocellular carcinoma (HCC) worldwide, and continue to represent a major challenge despite the growing contribution of alcohol-related and metabolic dysfunction-associated steatotic liver disease. Direct-acting antivirals now cure most patients with chronic HCV infection, while nucleos(t)ide analogues durably suppress HBV replication, producing a rapidly expanding population of treated and cured patients. Many nonetheless retain residual fibrosis, portal hypertension and long-term cancer risk, creating a need for non-invasive long-term liver assessment. Multiparametric ultrasound (MPUS) integrates the evaluation of morphology, fibrosis, steatosis, haemodynamics and perfusion within a single examination. This narrative review summarises the evidence supporting MPUS in chronic viral hepatitis, covering elastographic fibrosis assessment, Baveno VII liver and spleen stiffness criteria for clinically significant portal hypertension, contrast-enhanced ultrasound characterisation of focal liver lesions, and emerging techniques such as microvascular and viscosity-sensitive imaging. Particular attention is given to the confounding effect of inflammatory activity on liver stiffness. MPUS is presented here as a proposed evaluation framework for organising complementary measurements within a single examination, and not as an approach of demonstrated clinical superiority: no comparative or outcome-based study has yet shown that acquiring these parameters together improves clinical decisions relative to the individual techniques applied according to current guidelines. Within this framework, the most plausible role of MPUS in the elimination era is longitudinal assessment of the treated liver, a proposition that requires prospective validation against clinical endpoints. Full article

Background: Hepatocellular carcinoma (HCC) is a highly lethal malignancy and remains a major contributor to global cancer mortality. In situ vaccination (ISV) holds great potential for HCC therapy. Still, its efficacy is severely limited by intrinsic antigen scarcity and the tumor-associated macrophage (TAM)-mediated inhibition of dendritic cell (DC) maturation and T cell activation. In particular, the M2 TAM-HCC cell crosstalk may further aggravate ISV suppression. Moreover, as an internal organ tumor, HCC requires systemic administration of ISV agents, which often cause severe off-target toxicity. Methods: To address these challenges, we developed secretory phospholipase A2 (sPLA₂)-responsive liposomes co-loaded with the TLR7/8 agonist R848 and the ICD inducer doxorubicin (DOX) via a sequential remote loading method, termed sP-Lips@DR. Results: Incorporation of cholesterol (CHOL) significantly improved DOX encapsulation, and the sequential loading method enabled efficient co-encapsulation of both R848 and DOX. sP-Lips@DR responds to an sPLA₂-overexpressed, mildly acidic microenvironment in HCC, enabling selective drug release. In addition, sP-Lips@DR exhibited sPLA₂-responsive cytotoxicity toward H22 cells and macrophage phenotypic shift. Furthermore, sP-Lips@DR could disrupt the crosstalk between M2-like macrophages and H22 cells in an sPLA₂-responsive manner. Conclusions: Overall, the preparation and in vitro evaluation of sP-Lips@DR demonstrate their potential to enhance ISV efficacy in HCC, providing a solid foundation for future in vivo investigations. Full article

Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide and remains a major therapeutic challenge due to its marked inter- and intratumoral heterogeneity, diverse etiologies, and high propensity for therapeutic resistance. This review summarizes the biological complexity of HCC and current therapeutic challenges, with a particular focus on the RNA-binding protein human antigen R (HuR) as an emerging therapeutic target. Methods: A comprehensive narrative review of peer-reviewed literature was conducted, focusing on HCC pathogenesis, molecular heterogeneity, tumor microenvironment, mechanisms of therapeutic resistance, and recent advances in treatment. Emphasis was placed on studies investigating the biological functions of HuR and its therapeutic potential in HCC. Results: HCC progression is driven by complex interactions among genetic, epigenetic, metabolic, and environmental factors, resulting in substantial tumor heterogeneity and variable therapeutic responses. Dysregulated oncogenic signaling and immunosuppressive tumor microenvironment collectively contribute to resistance against current therapies, including multikinase inhibitors and immune checkpoint inhibitors. Although emerging strategies, such as combination immunotherapy, metabolic targeting, epigenetic modulation, and precision medicine, have shown encouraging preclinical and clinical results, their efficacy remains limited by tumor complexity and adaptive resistance. HuR functions as a master post-transcriptional regulator that stabilizes and promotes the translation of numerous mRNAs encoding oncogenic, inflammatory, and pro-survival factors. Accumulating preclinical evidence demonstrates that pharmacological inhibition of HuR suppresses multiple tumor-promoting pathways and enhances therapeutic sensitivity, supporting its potential as a novel therapeutic strategy for HCC. Conclusions: The biological complexity of HCC necessitates multifaceted, precision-based therapeutic approaches. Although additional HCC-specific mechanistic and translational studies are needed, targeting HuR represents a promising strategy to overcome tumor heterogeneity, therapeutic resistance, and disease progression. Continued integration of molecular profiling, advanced omics technologies, and rational combination therapies will be essential for translating these advances into improved clinical outcomes for patients with HCC. Full article