Exosomal miR-6126 as a novel therapeutic target for overcoming resistance of anti-cancer effect in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) stands as the sixth most prevalent cancer globally, presenting a substantial health challenge, particularly due to late-stage diagnoses that limit treatment effectiveness. Sorafenib, a multi-kinase inhibitor, is the primary chemotherapeutic agent for advanced HCC, but it only extends survival by 2-3 months. However, drug resistance remains a major clinical challenge, necessitating the exploration of new molecular mechanisms, including the role of microRNAs (miRNAs) in sorafenib resistance. In this study, we aimed to identify miRNAs within exosomes derived from sorafenib-resistant HCC cells to elucidate the molecular mechanisms underlying resistance. METHODS: Sorafenib-resistant cells were generated by culturing the human HCC cell line Huh7 in a medium containing 20 µM sorafenib for six months. Exosomes were isolated from the conditioned medium 24 h before cell harvest using exosome-depleted serum medium. miRNA sequencing and western blotting were used to analyze the expression profiles of exosomal miRNAs and proteins, respectively. pH measurement was performed to assess pH changes in response to sorafenib treatment and miRNA modulation. RESULTS: A total of 180 exosomal miRNAs were found to be dysregulated between sorafenib-treated control Huh7 (Huh7S) and sorafenib-resistant Huh7 (Huh7RS) cells, as well as between untreated control Huh7 and Huh7RS cells. Among these, miR-6126 was significantly downregulated in Huh7RS cells compared to Huh7S cells. Functional studies using 2-dimensional (D) and 3D cell culture systems revealed that miR-6126 overexpression reduced sorafenib resistance in Huh7RS cells, while its inhibition increased resistance in Huh7 cells. miR-6126 downregulated key proteins involved in cancer stem cell maintenance, such as CD44 and HK2. Furthermore, the pH level was elevated in cells overexpressing miR-6126 following sorafenib treatment, whereas inhibiting miR-6126 resulted in a lower pH. CONCLUSIONS: Exosomal miR-6126 plays a pivotal role in sorafenib resistance and tumorigenesis, highlighting its potential as a novel therapeutic target for overcoming drug resistance in HCC.

Candidate genes in canine hepatocellular carcinoma for molecular targeted therapy.

OBJECTIVES: Unresectable canine hepatocellular carcinoma (HCC) has limited nonsurgical treatment options. Sorafenib is a targeted therapy for unresectable canine HCC. However, there are limited reports on the expression of target genes. Therefore, the efficacy of the targeted therapies for canine HCC remains unclear. DATA DESCRIPTION: Liver specimens were obtained from 11 dogs with HCC and four dogs without HCC. We performed RNA seq using the mRNA extracted from the specimens. Differentially expressed genes (DEGs) between canine HCC and normal liver were explored based on previously reported molecular-targeted agents for human tumours. PARP3, DNMT1, FGF19, FGF23, and RET DEGs were upregulated, whereas KIT, FGFR2, and FGF21 DEGs were downregulated.

A CIA strategy with eminent drug-loading capacities for tumor ferroptosis-gas synergistic therapy.

Rationale: A common challenge of drug loading and delivery using magnetic resonance imaging (MRI) contrast agents (CAs) is the tendency of aggregation and precipitation at high drug loading conditions. Herein, we propose a generic strategy of controlled ideal aggregation (CIA) to restrict the tendency. Methods: Fe2+, ß-Lapachone (LAP), brequinar (BQR), or Sorafenib (SOR) was respectively loaded onto Gd poly (acrylic acid) macrochelate (GP), an MRI CA, in the hollow core of nitrite-modified hollow mesoporous organosilica nanoparticles (HMON-SNO). The aggregation of FeGP, LAPGP, BQRGP, and SORGP was controlled to be ideal without precipitation by the fixed space of the HMON-SNO hollow core. The sizes of the ideal aggregates are larger than the mesopore size of HMON-SNO, which prevents premature drug leakage and release. Results: After the accumulation of FeGP@HMON-SNO in tumors, the presence of glutathione (GSH) in the tumor microenvironment (TME) triggers the HMON-SNO degradation to release NO, Fe2+, and GP. The released Fe2+ reacts with endogenous hydrogen peroxide (H2O2) to generate Fe3+ and hydroxyl radical (•OH). The -SNO groups on the surface of HMON-SNO react with GSH, enabling sustained NO generation. The elevated NO level induces mitochondrial dysfunction, down-regulates lipid droplets through the alleviation of hypoxia and consequently promotes the accumulation of lipid peroxidation (LPO) under excess •OH to induce tumor cell ferroptosis. Moreover, the released GP facilitates high contrast T 1-weighted MRI of tumors due to its high r 1 value, enabling real-time monitoring for the in vivo delivery of FeGP@HMON-SNO. Conclusions: The proposed strategy of CIA with universality was successfully utilized to restrict the aggregation of MRI CAs at high drug loading conditions. The developed FeGP@HMON-SNO with eminent drug loading content were used for tumor ferroptosis-gas synergistic therapy with high efficacy.

Camrelizumab plus rivoceranib compared sorafenib as first-line therapeutic options for advanced hepatocellular carcinoma in China: a cost-effectiveness analysis.

AIM: The objective of this research is to assess the cost-effectiveness of combining camrelizumab with rivoceranib in comparison to sorafenib as first-line therapeutic options for advanced hepatocellular carcinoma from the Chinese medical system perspective. METHODS: A partitioned survival model was employed to perform a comprehensive cost-effectiveness analysis. This analysis incorporated multiple factors, such as treatment effectiveness, adverse events and costs, all of which were derived from data obtained from the CARES-310 trial. Furthermore, sensitivity analyses were conducted to evaluate the robustness and reliability of the model. RESULTS: The comparison between the two groups demonstrated that the cohort receiving camrelizumab combined with rivoceranib exhibited a significant increase of 0.803 quality-adjusted life year (QALY), alongside an additional expenditure of US$7345.051. This computation resulted in an incremental cost-effectiveness ratio of US$9147.012 per QALY, which was lower than the willingness-to-pay threshold of US$39 855.785 per QALY in China. Sensitivity analyses conducted in this study further demonstrated the robustness of the results across various assumptions. CONCLUSION: The adoption of camrelizumab plus rivoceranib as a treatment option is not only associated with improved health outcomes but also represents a cost-effective choice in China.

PD-1/PD-L1 Inhibitors Plus Antiangiogenic Drugs Versus Sorafenib as the First Line Treatment for Advanced Hepatocellular Carcinoma: A Phase 3 RCTs Based Meta-Analysis.

BACKGROUND: For advanced hepatocellular carcinoma (HCC), sorafenib remains the established therapy. PD-1/PD-L1 inhibitors plus antiangiogenic drugs (PIAD) as a new therapeutic approach for advanced HCC is still a subject of clinical debate regarding whether they offer improved treatment outcomes. This study was conducted to compare the two treatments in terms of antitumor efficacy and safety. METHODS: Randomized controlled trials (RCTs) comparing PIAD and sorafenib for advanced HCC were retrieved from six databases. Survival (overall survival [OS] and progression-free survival [PFS]) were the main outcomes measured. Secondary endpoints included responses, adverse events (AEs), and effects on quality of life. RESULTS: Seven studies based on four RCTs (CARES-310, COSMIC-312, IMbrave150, and ORIENT-32) were included. The PIAD group exhibited better OS (hazard ratio [HR]: 0.69, 95% confidence interval [CI]: [0.53, 0.89], P = 0.005), and PFS (HR: 0.60, 95% CI: [0.53, 0.67], P < 0.00001). The survival advantages of OS and PFS were confirmed in almost all subgroups. The PIAD group exhibited higher OS rates at 6-18 months and PFS rates at 6-12 months. Additionally, the objective response rate, disease control rate, complete response, and partial response were higher in PIAD group. The PIAD group had a delayed decline in quality of life, physical functioning, and role functioning. However, the PIAD group experienced more grades 3-5 and serious AEs, along with treatment discontinuation, dose reduction, and dose interruption. CONCLUSIONS: PIAD appears to be better than sorafenib for advanced HCC with better survival and responses. However, its higher rate of AEs requires cautious attention.

Hepatic arterial infusion chemotherapy plus regorafenib compared with regorafenib alone as second-line therapy for advanced hepatocellular carcinoma: a randomised controlled trial protocol.

INTRODUCTION: The exact role of hepatic arterial infusion chemotherapy (HAIC) in advanced hepatocellular carcinoma (aHCC) is still unknown. The combination of HAIC and sorafenib has been proven to be more effective than sorafenib alone in the first-line treatment of aHCC. The aim of the study is to evaluate the efficacy and safety of HAIC plus regorafenib in the second-line treatment of aHCC. METHODS AND ANALYSIS: This is a multicenter, open-label, randomised controlled phase III trial. A total of 294 patients with aHCC, who are unable to tolerate the first-line systemic therapy or progress after the first-line systemic therapy, will be enrolled in the study. The patients will be randomly (2:1) assigned into the combination treatment group (HAIC plus regorafenib, n=196) and the control group (regorafenib alone, n=98). HAIC and regorafenib (160 mg/day) will be given in a 4-week cycle. The primary endpoint is overall survival in the intention-to-treat population. The second endpoints include progression-free survival, overall response rate, time to progression, etc. The radiological assessments will be based on the criteria of Response Evaluation Criteria in Solid Tumors 1.1. ETHICS AND DISSEMINATION: This study is approved by the ethics committee of Cancer Hospital, Chinese Academy of Medical Sciences. All participants are required to provide written informed consent. The results of this study will be disseminated through peer-reviewed publications and esteemed academic conferences. TRIAL REGISTRATION NUMBER: Chinese Clinical Trial Registry (ChiCTR2300073075).

Real-World, Observational, Retrospective Study to Evaluate the Effectiveness and Safety of Treatment with Sorafenib in Patients with Advanced Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) accounts for approximately 90% of liver cancer cases. Sorafenib, the first drug to demonstrate survival benefits for advanced HCC, was validated through the SHARP randomized clinical trial (RCT). While RCTs are essential for assessing new therapies, real-world studies provide additional insights into their effectiveness in routine clinical practice. This study aimed to evaluate sorafenib's real-world effectiveness by analyzing overall survival (OS) and the time to radiological and symptomatic progression. METHODS: Data from 368 patients treated with sorafenib at a Brazilian Cancer Center between 2009 and 2020 were retrospectively reviewed. RESULTS: The median OS was 9.6 months, and the time to radiological progression was 5.3 months, similar to the SHARP trial. However, the time to symptomatic progression was shorter (2.3 months) than the SHARP study (4.1 months). In terms of safety, 27.4% of patients presented clinically relevant toxicities, and 24.5% needed to discontinue treatment due to toxicity. CONCLUSIONS: Overall, sorafenib demonstrated effectiveness in the studied population, with OS and radiological progression times comparable to SHARP study results. The difference in symptomatic progression may be due to the study's retrospective nature and limitations.

Engineering Strain-Defects to Enhance Enzymatic Therapy and Induce Ferroptosis.

The effect of mimetic enzyme catalysis is often limited by insufficient activity and a single therapy is not sufficient to meet the application requirements. In this study, a multifunctional nanozyme, MMSR-pS-PEG, is designed and fabricated by modifying poly (ethylene glycol) grafted phosphorylated serine (pS-PEG) on mesoporous hollow MnMoOx spheres, followed by loading sorafenib (SRF) into the pores. Strain engineering-induced oxygen defects endow the nanozyme with enhanced dual-enzymatic activity to mimic catalase and oxidase-like activities, which catalyze the conversion of endogenous H2O2 into oxygen and subsequently into superoxide ions in the acidic tumor microenvironment. Moreover, as an n-type semiconductor, MnMoOx generates reactive oxygen species by separating electrons and holes upon ultrasonic irradiation and simultaneously deplete glutathione by holes, thereby further augmenting its catalytic effect. As a ferroptosis inducer, SRF restrains the system xc - and indirectly inhibits glutathione synthesis, synergistically interacting with the nanozyme to stimulate ferroptosis by promoting lipid peroxidation and accumulation and the downregulation of glutathione peroxidase 4. These results provide valuable insights into the design of enzymatic therapy with high performance and highlight a promising approach for the synergism of ferroptosis and enzymatic tumor therapy.

N6-Methyladenosine modification activates the serine synthesis pathway to mediate therapeutic resistance in liver cancer.

Metabolic adaptation serves as a significant driving force for cancer growth and poses a substantial obstacle for cancer therapies. Herein, we unraveled the role of m6A-mediated serine synthesis pathway (SSP) regulation in both hepatocellular carcinoma (HCC) development and therapeutic resistance. We demonstrated that treatment of highly specific m6A inhibitor (STM2457) effectively inhibited HCC cell line growth and suppressed spontaneous HCC formation in mice driven by liver-specific Tp53 knockout and Myc overexpression. Using GLORI-seq, we delineated a single-base-resolution m6A landscape in human HCC cell lines. Interestingly, we identified three core enzymes in the SSP (PHGDH, PSAT1, and PSPH) as novel targets of METTL3-mediated m6A modification. In these SSP genes, m6A modification recruited m6A reader IGF2BP3 to stabilize their mRNA transcripts, thereby enhancing their mRNA and protein expression in HCC cells. Most importantly, our GLORI-seq data revealed that sorafenib-resistant HCC cells elevated m6A modification in SSP genes to promote protein expression and antioxidant production. STM2457 treatment attenuated the serine synthesis pathway, induced oxidative stress, and sensitized HCC cells to sorafenib and lenvatinib treatments. In conclusion, our findings suggest that targeting m6A could be a potential therapeutic strategy for HCC treatment.

Effectiveness of sorafenib in treating intermediate-stage hepatocellular carcinoma patients refractory to transarterial chemoembolization.

BACKGROUND: Switching to systemic therapy after transarterial chemoembolization (TACE) refractoriness is more inclined to preserve liver function and decrease disease progression. Hence, we conducted a comparison between the advantages of sorafenib therapy and the continuation of TACE in patients with intermediate-stage hepatocellular carcinoma (HCC) who developed TACE refractoriness. METHODS: This retrospective cohort work involved 1,200 patients with HCC who received TACE therapy at our institution between January 2018 and December 2022. Out of these, a total of 436 participants were determined to be resistant to TACE treatment throughout their clinical progression. Out of them, 271 were finally included and categorized into two groups: (1) patients who shifted from TACE to sorafenib, and (2) patients who maintained TACE treatment. The study assessed the overall survival (OS) and time to disease progression (TTDP) of patients who were resistant to TACE, comparing both groups based on when they achieved Child-Pugh C or acquired advanced-stage HCC. RESULTS: Following confirmation of refractoriness to TACE therapy, 163 opted to continue with TACE (TACE group), whereas 108 shifted to sorafenib treatment (sorafenib group). The median TTDP was 23.36 months, while the median OS was 25.3 months, in the sorafenib group, and 11.6 and 14.2 months, correspondingly, in the TACE group (p = 0.0001). CONCLUSION: Switching to sorafenib treatment significantly improved OS and TTDP in patients with intermediate-stage HCC who were refractory to TACE. These finding highlights sorafenib's potential as an effective alternative for managing disease progression in patients unresponsive to TACE, offering a valuable treatment option in this challenging clinical scenario.

Synergistic anticancer efficacy of polydatin and sorafenib against the MCF-7 breast cancer cell line via inhibiting of PI3K/AKT/mTOR pathway and reducing resistance to treatment.

Polydatin (PD), a glucoside derivative of resveratrol, has been investigated for its potential to mitigate sorafenib (SOF) side effects and combat multidrug resistance in cancer treatment. The study evaluated its mechanism of action for inhibiting the protein kinase B/mTOR pathway in promoting breast cancer proliferation. The combined PD and SOF have synergistic effects with a combination index (CI) < 1 in the liver (HepG2) and breast (MCF-7) cancer cell lines. Molecular docking studies were conducted to analyze interactions of PD& SOF with protein kinases as well as apoptotic and multidrug resistance proteins, including AKT1, PI3K, mTOR, Apaf-1, and ABCB1 in MCF-7 cells. Experimental validation through real-time PCR confirmed. PD has a strong binding affinity, particularly with AKT1 (-56 kcal/mol) and ABCB1 (-27.16 kcal/mol), a gene associated with multidrug resistance. These interactions were linked to anti-proliferative anti-angiogenic effects and reduced resistance to treatment, demonstrating PD has potential therapeutic benefits. Furthermore, PD combined with SOF induced apoptosis, inhibited cell growth, and arrested MCF-7 cells in the sub-G1 phase with increased intracellular ROS. This was accompanied by reduced expression of AKT1 and ABCB1 genes, reinforcing the anticancer efficacy of PD/SOF combination therapy. In conclusion, the findings suggest that PD/SOF could serve as a promising anticancer treatment strategy, warranting further investigation for potential clinical applications and mechanistic studies in vivo.

A novel goldfish orthotopic xenograft model of hepatocellular carcinoma developed to evaluate antitumor drug efficacy.

Tumor xenograft animal models play a crucial role in hepatocellular carcinoma (HCC) research. Mice xenograft models are time consuming, laborious and expensive while zebrafish tumor xenograft models are cost-effective and effortless. However, the development of orthotopic xenograft models for HCC in zebrafish embryos has been challenging due to the small size of zebrafish livers. In this study, we utilized 7-day-old goldfish embryos as hosts and successfully established an orthotopic xenograft model of HCC in goldfish livers. Through injecting fluorescence labeled HCC cells into the liver of goldfish, we could visualize the proliferation and migration of tumor cells in vivo. In addition, we found that the temperature of 36 °C was better for tumor cell survival in goldfish larvae compared to 28 °C, assessed by EdU and TUNEL assays. Moreover, macrophage infiltration in the goldfish liver could be evaluated by neutral red staining. Finally, we evaluated the efficacy of the targeted therapy drug Sorafenib and the traditional Chinese medicine, Huaier granules, alone or in combination in the goldfish HCC orthotopic xenograft model. We found that the combination therapy showed the best efficacy against HCC cells in terms of macrophage infiltration, polarization as well as tumor cells proliferation, metastasis and apoptosis. In conclusion, the proposed goldfish HCC orthotopic xenograft model opens new avenues for HCC related research, including evaluation of tumor progression, cell interactions in the immune microenvironment, drug efficacy, and screening of anti-tumor drugs.

Delivery of Avocado Seed Extract Using Novel Charge-Switchable Mesoporous Silica Nanoparticles with Galactose Surface Modified to Target Sorafenib-Resistant Hepatocellular Carcinoma.

Background: Sorafenib-resistant (SR) hepatocellular carcinoma (HCC) is a current serious problem in liver cancer treatment. Numerous phytochemicals derived from plants exhibit anticancer activity but have never been tested against drug-resistant cells. Methods: Avocado seed extract (APE) isolated by maceration was analysed for its phytochemical composition and anticancer activity. Novel design charge-switchable pH-responsive nanocarriers of aminated mesoporous silica nanoparticles with conjugated galactose (GMSN) were synthesised for delivering APE and their physicochemical properties were characterized. The drug loading efficiency (%LE) and entrapment efficiency (%EE) were evaluated. Anticancer activity of APE loaded GMSN was measured against HCC (HepG2, Huh-7) and SR-HCC (SR-HepG2). Results: Anticancer activity of APE against non-resistant HepG2 (IC50 50.9 ± 0.83 µg mL-1), Huh-7 (IC50 42.41 ± 1.88 µg mL-1), and SR-HepG2 (IC50 62.58 ± 2.29 µg mL-1) cells was confirmed. The APE loaded GMSN had a diameter of 131.41 ± 14.41 nm with 41.08 ± 2.09%LE and 44.96 ± 2.26%EE. Galactose functionalization (55%) did not perturb the original mesoporous structure. The GMSN imparted positive surface charges, 10.3 ± 0.61mV at acidic medium pH 5.5 along with rapid release of APE 45% in 2 h. The GMSN boosted cellular uptake by HepG2 and SR-HepG2 cells, whereas the amine functionalized facilitated their endosomal escape. Their anticancer activity was demonstrated in non-resistant HCC and SR-HCC cells with IC50 values at 30.73 ± 3.14 (HepG2), 21.86 ± 0.83 (Huh-7), 35.64 ± 1.34 (SR-HepG2) µg mL-1, respectively, in comparison to the control and non-encapsulated APE. Conclusion: APE loaded GMSN is highly effective against both non-resistant HCC and SR-HCC and warrants further in vivo investigation.

DNASE1L3-mediated PANoptosis enhances the efficacy of combination therapy for advanced hepatocellular carcinoma.

Rationale: The introduction of combination therapy utilizing tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors for advanced hepatocellular carcinoma (HCC) has significantly altered the management of affected patients. However, the absence of predictive biomarkers to identify those who would derive the greatest benefit from this combination therapy underscores the necessity for further enhancements in its efficacy. Methods: In this study, we performed a proteomic analysis on surgical specimens from patients who either responded to or did not respond to combination therapy with sorafenib and programmed death-1 (PD-1) monoclonal antibody (mAb). We employed in vitro experiments, including immunocytochemistry, co-immunoprecipitation, and transmission electron microscopy, to elucidate the mechanism of DNASE1L3-induced PANoptosis. Additionally, we assessed the function of DNASE1L3 in combination therapy using a mouse liver orthotopic tumor model and clinical samples. Results: Our findings indicated that the levels of deoxyribonuclease 1 like 3 (DNASE1L3) were significantly elevated in the cohort of patients who responded to treatment, correlating with the sorafenib-induced programmed cell death (PCD) of HCC cells. Further experimentation revealed that DNASE1L3 facilitated the generation of double-strand deoxyribonucleic acid (dsDNA) breaks and activated the absent in melanoma 2 (AIM2) pathway during sorafenib-induced HCC cell death, ultimately culminating in PANoptosis. Moreover, DNASE1L3-induced PANoptosis augmented the activation of anti-tumor immunity within the tumor microenvironment (TME), thereby enhancing the efficacy of the combination therapy involving sorafenib and PD-1 mAb. Conclusion: Our findings offer valuable insights into the mechanisms underlying DNASE1L3's role in sorafenib sensitivity and position DNASE1L3 as a promising predictive biomarker and target for improving outcomes in combination therapy for HCC.

Examining nirogacestat for adults with progressing desmoid tumors who require systemic treatment.

INTRODUCTION: Desmoid tumor (DT) is a rare, locally aggressive, mesenchymal neoplasm that can arise at any site in the body. Medical therapies play a major role for DT's patients requiring treatment. A novel systemic approach has recently emerged with Nirogacestat, a γ-secretase inhibitor targeting the NOTCH signaling pathway. AREAS COVERED: Nirogacestat is the first drug in its class to receive approval from the Food and Drug Administration (FDA) and is the first FDA-approved treatment specifically for DTs. We reviewed the data leading to its discovery, including its mechanism of action, pharmacological properties, clinical efficacy, and its positioning within the current treatment armamentarium for DTs. EXPERT OPINION: High-quality evidence for systemic therapies in the management of DTs remains an unmet need. Nirogacestat now joins sorafenib as the only drugs with efficacy in DTs demonstrated by randomized phase 3 studies. Currently, there are no comparative trials of the available systemic therapies. Therefore, physicians should consider factors such as drug accessibility, cost, toxicity profile, comorbidities, and patient preferences when selecting treatment. Long-term efficacy and safety data will be essential for evaluating the duration of treatment response and monitoring late-onset side effects of Nirogacestat.

Intracellular Magnetic Hyperthermia Sensitizes Sorafenib to Orthotopic Hepatocellular Carcinoma Via Amplified Ferroptosis.

Sorafenib (SRF) is recognized as the primary treatment for hepatocellular carcinoma (HCC), yet the emergence of SRF resistance in many HCC patients results in unfavorable outcomes. Enhancing the efficacy of SRF in HCC remains a significant challenge. SRF works in inducing ferroptosis, a form of cell death, in cancer cells through the inhibition of glutathione peroxidase 4 (GPX4). The effectiveness of this process is limited by the low levels of cellular iron and reactive oxygen species (ROS). A promising approach to circumvent this limitation is the use of intracellular magnetic hyperthermia (MH) mediated by magnetic iron oxide nanomaterials (MIONs). When MIONs are subjected to an alternating magnetic field (AMF), they heat up, enhancing the Fenton reaction, which in turn significantly increases the production of ROS within cells. In this study, we explore the capability of MH facilitated by high-performance ferrimagnetic vortex-domain iron oxide nanoring (FVIO) to enhance the effectiveness of SRF treatment in HCC. The increased iron uptake facilitated by FVIO significantly enhances the sensitivity of HCC cells to SRF-induced ferroptosis. Moreover, the nanoheat generated by FVIO in response to an AMF further elevates ROS levels and stimulates lipid hydroperoxide (LPO) production and GPX4 inactivation, thereby intensifying ferroptosis. Both in vitro and in vivo animal studies demonstrate that combining FVIO-mediated MH with SRF significantly reduces cell viability and inhibits tumor growth, primarily through enhanced ferroptosis, with minimal side effects. The effectiveness of this combination therapy is affected by the ferroptosis inhibitor ferrostatin-1 (Fer-1) and the iron chelator deferoxamine (DFO). The combination treatment of FVIO-mediated MH and SRF offers a strategy for HCC treatment by promoting accelerated ferroptosis, presenting a different perspective for the development of ferroptosis-based anticancer therapies.

Hepatic stellate cell-targeted chemo-gene therapy for liver fibrosis using fluorinated peptide-lipid hybrid nanoparticles.

Exploring precise and effective treatments for liver fibrosis is urgent. The effective therapy for liver fibrosis depends on the specific delivery of antifibrotic drugs to activated hepatic stellate cells (aHSCs). However, this is a challenging task due to pathological barriers, primarily caused by collagen deposition. This study developed vitamin A-functionalized fluorinated peptide/lipid hybrid nanoparticles to co-deliver sorafenib and siRNA against HSP47 (SF-siHSP47@VFPL NPs). This nanoparticle formulation offers significant advantages due to its fluorine­fluorine and electrostatic interactions, allowing for high SF and siHSP47 loading efficiency and sustained drug release. Importantly, in vitro cell uptake and in vivo biodistribution revealed that VA functionalization significantly improved aHSC-targeted delivery efficiency by engaging retinol-binding protein receptors on HSCs. Furthermore, it dramatically reduced extracellular matrix deposition, as evidenced by diminished levels of liver fibrosis-associated genes (HSP47, TIMP-1, and collagen I), promoting collagen breakdown and preventing collagen production, thus overcoming drug delivery barriers. Thus, SF-siHSP47@VFPL NPs demonstrated optimal antifibrotic effects by triggering apoptosis and ferroptosis in aHSCs. In liver fibrosis mouse models, SF-siHSP47@VFPL NPs remodeled the pathological environment and restored liver functionality through a marked reduction in serum liver transferases, hydroxyproline content, collagen deposition, and α-SMA and CD31 expression in liver tissue, resulting in alleviated liver fibrosis. Consequently, SF-siHSP47@VFPL NPs showed significant potential for HSC-targeted, chemo-gene therapy in the treatment of liver fibrosis.

DDR1 is a Novel Biomarker and Potential Therapeutic Target for the Combination Treatment of Liver Hepatocellular Carcinoma.

AIM: This study aimed to investigate the role of discoidin domain receptor tyrosine kinase 1 (DDR1) in liver hepatocellular carcinoma (LIHC) and to evaluate its prognostic value on patient response to combination therapy. METHODS: In the current retrospective study, we examined the protein expression of DDR1 in various cancers by standard immunohistochemical (IHC) methods and evaluated its clinical significance in LIHC personalized treatment. Multiple online databases, including The Cancer Genome Atlas (TCGA), TIMER, GEO, ROC Plotter, and Genomics of Drug Sensitivity in Cancer (GDSC), were used. RESULTS: DDR1 protein expression was higher in LIHC than in other nine examined cancer types. Additionally, DDR1 exhibited higher expression levels in adjacent normal tissues compared to HBs-positive LIHC tissues. Analysis at single-cell resolution revealed that DDR1 was expressed primarily in epithelial cells but not in stromal and immune cells, and DDR1 expression was lower in HBs-positive LIHC cells in comparison with normal hepatocytes. Correlation of DDR1 upregulation and sorafenib resistance was observed in the patient cohort. Moreover, DDR1 expression positively correlated with the expression of inflammatory response-related genes, ECM-related genes, and collagen formation-related genes, but negatively correlated with the infiltration of CD8+ T cells, NK cells, and dendritic cells in LIHC. CONCLUSIONS: Our findings suggest that DDR1 expression might be induced by collagen production-related cellular events involved in liver injury and repair, and that DDR1 overexpression might contribute to the resistance to LIHC targeted therapy and immunotherapy, highlighting DDR1 as a potential prognostic biomarker and therapeutic target.

This study aimed to investigate the role of discoidin domain receptor tyrosine kinase 1 (DDR1) in liver hepatocellular carcinoma (LIHC) and to evaluate its prognostic value on patient response to combination therapy. In the current retrospective study, we examined the protein expression of DDR1 in various cancers by standard immunohistochemical (IHC) methods and evaluated its clinical significance in LIHC personalized treatment. Multiple online databases, including The Cancer Genome Atlas (TCGA), TIMER, GEO, ROC Plotter, and Genomics of Drug Sensitivity in Cancer (GDSC), were used. DDR1 protein expression was higher in LIHC than in other nine examined cancer types. Additionally, DDR1 exhibited higher expression levels in adjacent normal tissues compared to HBs-positive LIHC tissues. Analysis at single-cell resolution revealed that DDR1 was expressed primarily in epithelial cells but not stromal cells and immune cells, and DDR1 expression was lower in HBs-positive LIHC cells in comparison with normal hepatocytes. Correlation of DDR1 upregulation and sorafenib resistance was observed in patient cohort. Moreover, DDR1 expression positively correlated with the expression of inflammatory response-related genes, ECM-related genes, and collagen formation-related genes but negatively correlated with the infiltration of CD8 + T cells, NK cells, and dendritic cells in LIHC. Our findings suggest that DDR1 expression might be induced by collagen production-related cellular events involved in liver injury and repair and that DDR1 overexpression might contribute to the resistance to LIHC targeted therapy and immunotherapy, highlighting DDR1 as a potential prognostic biomarker and therapeutic target.

Efficacy of sorafenib plus transcatheter arterial chemoembolization in treating hepatocellular carcinoma with portal vein tumor thrombosis: A meta-analysis.

This meta-analysis aimed to evaluate the efficacy of sorafenib plus transcatheter arterial chemoembolization (TACE) in treating hepato-cellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT). Twelve randomized controlled trials published until 28th Sep 2022 were finally included. Of the total 1746 patients, of whom 458 received sorafenib and TACE treatment (Group S+TACE), and 1288 only underwent TACE (Group TACE), were enrolled. Outcomes including time to progression (TTP), objective response rate (ORR), disease control rate (DCR), overall survival (OS), survival rate (SR), and adverse reactions, were extracted. The OS (HR: 0.596, 95 %CI: 0.507-0.685, p < 0.001; I2 = 0.0 %) and TTP (HR: 0.379, 95 %CI: 0.205-0.553, p < 0.001; I2 = 4.5 %) in the S+TACE group were longer than those in the TACE group. The ORR (RR: 2.101, 95 %CI: 1.555-2.839, p < 0.001; I2 = 0.0 %), DCR (RR: 1.547, 95 %CI: 1.126-2.126, p = 0.007; I2 = 79.6 %) and SR (RR: 1.416, 95 %CI: 1.183-1.694, p < 0.001; I2 = 83.8 %) in the S+TACE group were higher than those in the TACE group. Compared with the TCAE group, the higher odds of HFSR, oral ulcer, and diarrhea among patients with HCC complicated by PVTT were discovered in the S+TACE group. The marginal significance was found in ascites and gastrointestinal bleeding between the two groups. Sorafenib plus TACE has good efficacy and mild adverse reactions, which may be worthy of clinical promotion.