Combinatorial Use Research Articles

Identification of Phytosphingosine-Based 1-O-Acylceramide in Human Stratum Corneum and Investigation of Its Role in Skin Barrier

Phytosphingosine-based 1-O-acylceramide (CerENP) from the human stratum corneum has not been reported on. High-resolution mass spectrometry was used to identify CerENP from skin samples. A vehicle-controlled human study was performed to investigate the physiological interaction between ceramide NP (CerNP) and CerENP with respect to skin hydration, cohesion, and TEWL, all of which were measured. Twenty volunteers were treated with test creams containing CerENP together with CerNP, which significantly improved skin barrier parameters after four weeks of application: 1. Skin hydration was increased by 26% compared to when CerNP was used alone, and moisture retention was better than it was with the CerNP control. 2. Stratum corneum (SC) cohesion was strengthened significantly only when using the test cream formulated with CerENP. The results suggested the boosting effects of CerENP on the skin barrier functions exerted by CerNP since only a small amount is required, as low as one-tenth of CerNP. This is the first report on the identification of CerENP in the human SC and its skin barrier activities in human skin. In conclusion, the combinatorial use of CerENP and CerNP at an appropriate relative ratio could be a new normal in developing an ideal moisturizer for dry and atopic skin.

Fast Screening Libraries of Plant Growth Promoting Rhizobacteria (PGPRs) for Insecticidal Activity.

Plant Growth Promoting Rhizobacteria (PGPR) are ubiquitous among soil bacteria and aid in many growth-related functions for plants. Recent biotechnological advancements involving PGPRs have led to a growing desire to explore and uncover combinatorial or dual use PGPRs. Our study aimed to discover novel insecticidal phenotypes amongst PGPR libraries. We screened, through survivorship bioassays, 502 endophytic PGPRs for insecticidal activity against Drosophila melanogaster (fruit flies). Initial bioassay screens were followed by higher (n) testing and subsequent insecticidal assays against 4 key pest species including Drosophila suzukii, Spodoptera frugiperda, Aphis gossypii, and Lygus lineolaris. Of the 502 endophytic PGPRs screened, 39 strains showed statistically significant mortality against insects with three strains killing four pest species and seven killing three pest species. The key insecticidal strains primarily consisted of Serratia marcescens and Bacillus velezensis. In total, ∼8% of strains tested showed insecticidal phenotypes. The fast screening methodology was successful in uncovering dual use PGPRs. Some bacteria were broad spectrum insect killers and others were more specific to a particular pest.

Asparagine drives immune evasion in bladder cancer via RIG-I stability and type I IFN signaling.

Tumor cells often employ many ways to restrain type I interferon signaling to evade immune surveillance. However, whether cellular amino acid metabolism regulate this process remains unclear and its effects on antitumor immunity are relatively unexplored. Here, we find that asparagine inhibits IFN-I signaling and promotes immune escape in bladder cancer. Depletion of asparagine synthetase (ASNS) strongly limits in vivo tumor growth in a CD8+ T cell-dependent manner and boosts immunotherapy efficacy. Moreover, clinically approved ASNase synergizes with anti-PD-1 therapy in suppressing tumor growth. Mechanistically, asparagine can directly bind to RIG-I and facilitate CBL-mediated RIG-I degradation, thereby suppressing IFN signaling and antitumor immune responses. Clinically, tumors with higher ASNS expression show decreased responsiveness to ICIs therapy. Together, our findings uncover asparagine as a natural metabolite to modulate RIG-I-mediated IFN-I signaling, providing the basis for developing the combinatorial use of ASNase and anti-PD-1 for bladder cancer.

BRD1 deficiency affects SREBF1-related lipid metabolism through regulating H3K9ac/H3K9me3 transition to inhibit HCC progression

BRD1 encodes a protein containing a bromodomain, which is an essential component of histone acetyltransferase (HAT) complexes. These complexes play a crucial role in the regulation of gene transcription and the modification of chromatin structures. The aberrant expression of BRD1 is frequently observed across a range of cancer types, including hepatocellular carcinomas (HCC). However, the precise mechanisms through which BRD1 contributes to tumorigenesis, especially in HCC, remain unclear. In our investigation, we have uncovered a novel role for BRD1 as an oncogene implicated the regulation of lipid metabolism in HCC progression. Specifically, the deficiency of BRD1 impedes the proliferation and metastasis of HCC cells reducing the accumulation of lipid droplets and cholesterol levels. This effect is mediated through the SREBF1-induced downregulation of SCD1 expression in HCC cells. Mechanistically, the ablation of BRD1 disrupts acetylation level of H3K9, culminating in the subsequent trimethylation of H3K9 (H3K9me3). Notably, the H3K14ac partially colocalizes with H3K9me3 and its methyltransferase SETDB1 to from a double labeling of both H3K14ac and H3K9me3 at the SREBF1 promoter. This double labeling contributes to the creation of a repressive environment, ultimately leading to the downregulation of SREBF1 gene expression in HCC. Furthermore, the combinatorial use of a BRD1 inhibitor and simvastatin augments antitumor efficacy in vivo. Collectively, our findings underscore BRD1 as a critical regulator of SREBF1-associated lipid metabolism and a participant in HCC progression through a distinct epigenetic regulatory mechanism. These discoveries further suggest a promising epigenetic therapeutic approach for the treatment of HCC.

Selective JAK2 pathway inhibition enhances anti-leukemic functionality in CD19 CAR-T cells

The integration of molecular targeted therapeutics with chimeric antigen receptor T (CAR-T) cell therapy represents a novel strategy to amplify the anti-tumor efficacy of immunotherapy. While CD19-targeted CAR-T cells and Janus kinase (JAK) inhibitors have independently shown efficacy against certain B-cell leukemias, such as Philadelphia chromosome-like acute lymphoblastic leukemia, the concurrent use of JAK1/2 inhibitors, such as ruxolitinib, has been implicated in reducing CAR-T cell potency by inhibiting the JAK1-dependent T cell activation pathway. This study explores the combinatorial use of a selective type II JAK2 inhibitor, CHZ868, with CD19 CAR-T cells, revealing a synergistic enhancement of anti-leukemic activity across B-cell tumor models irrespective of JAK2 mutational status. CHZ868-mediated JAK2 inhibition did not induce the exhaustion of CAR-T cells, maintaining efficacy over repeated tumor challenges and significantly extending survival in mouse models engrafted with JAK2 inhibitor-resistant leukemia cells (median survival, CD19 CAR-T + CHZ868 vs. CD19 CAR-T + DMSO: 32 days vs. 26 days, p = 0.0303). Transcriptomic analyses suggest that CHZ868 impedes CAR-T cell differentiation while preserving their proliferative capacity, a crucial factor in maintaining CAR-T cell functionality. Therefore, the selective inhibition of the JAK2 pathway may potentiate CAR-T cell therapy and offer a viable treatment strategy for patients with resistant B-cell leukemias.

The Mixed Transition-Metal Cyanamide MnCr2(NCN)4.

The ternary transition-metal cyanamide MnCr2(NCN)4 was synthesized by a solid-state metathesis reaction between MnCl2, CrCl3, and ZnNCN. Powder X-ray diffraction reveals that MnCr2(NCN)4 adopts an orthorhombic [NiAs]-derived structure with Pbcn symmetry, featuring a hexagonally close-packed array of NCN2- with metal cations in 3/4 of the octahedral interstitial holes. The question of cation order was addressed via the combinatorial use of X-ray powder diffraction, neutron powder diffraction, electron diffraction, and HAADF-STEM measurements. These studies support an average structure with complete ordering of Mn2+ and Cr3+ in single and double corrugated rows of like cations, respectively. HAADF images, however, suggest locally a degree of cation disorder, especially at the manganese site. UV-vis and XANES measurements confirm the assignment of divalent manganese and trivalent chromium, whereas IR spectroscopy reveals the presence of cyanamide-type NCN2- moieties with a degree of single and triple bond character due to the asymmetric coordination that is distorted away from the regular trigonal prismatic coordination encountered in the CoNCN aristotype due to vacancy and cation order. Finally, SQUID magnetometry unearths predominantly antiferromagnetic interactions with a transition to what appears to be a ferrimagnetically ordered state below 160 K.

Analysis of engineered T7 bacteriophages containing genetic sequences encoding antimicrobial peptides.

Because of the global spread of multi- and pan-resistant bacteria, there is a need to identify, research, and develop new strategies to combat these pathogens. In a previous proof-of-concept study, we presented an innovative strategy by genetically modifying lytic T7 bacteriophages. We integrated DNA fragments encoding for derivatives of the antimicrobial peptide (AMP) apidaecin into the phage genome to induce the production and release of apidaecin within the T7 infection cycle, thereby also targeting phage-resistant Escherichia coli bacteria. In this follow-up study, we optimized the apidaecin encoding insert to improve the expression of the apidaecin derivative Api805 by adding the secretion signal peptide of the OmpA protein. This prevented the detrimental effects of the peptide on the producing bacterial cell after its production. The integration of two copies of the OmpA-Api805 insert into the phage genome resulted in T7Select-2xOmpA-Api805 phages, which had a partially improved activity in inhibiting phage-resistant E. coli compared to the T7Select phages without insert and with only one copy of the OmpA-Api805 insert. Additionally, we showed that the combinatorial use of the lytic bacteriophage T7Select with the highly active and lytic AMPs CRAMP (cathelicidin-related AMP) and melittin against E. coli made the lysis process of the phage and the peptides more effective and prevented the growth of potentially AMP- and phage-resistant E. coli strains. The integration of DNA sequences derived from CRAMP and melittin into the phage genome resulted in the created T7Select-(M)CRAMP and T7Select-(M)melittin phages, which showed a lysis behavior like the phage without insert and partially inhibited the growth of potentially phage-resistant E. coli strains after the phage-mediated lysis.

Re-arranging the Cis-regulatory Modules of Hox Complex in Drosophila via FLP-FRT and CRISPR/Cas9.

FLP-FRT, a well-established technique for genome manipulation, and the revolutionary CRISPR/Cas9, known for its targeted indels, are combined in a novel approach. This unique method is applied to the Hox genes in the Drosophila melanogaster bithorax complex, which are closely located to the cis-regulatory modules that define their spatial-temporal regulation. The number and position of these genes are directly correlated to their expression pattern. This chapter unveils the exciting potential of this combinatorial use of FLP-FRT and CRISPR-Cas9 to rearrange the cis-regulatory modules of the Hox complex in Drosophila melanogaster.

Innovative Organic Fertilizers and Cover Crops: Perspectives for Sustainable Agriculture in the Era of Climate Change and Organic Agriculture

Anthropogenic activities have resulted in land desertification in various regions of the world, leading to the degradation of critical soil characteristics such as organic matter (OM) content, nutrient stock, and prevailing biodiversity. Restoring such degraded soils through organic matter amendments and diversified crop rotations is thus an intrinsic part of organic farming. This review discusses a wide range of organic farming impacts on soil health and crop productivity by focusing on organic fertilizers and crop diversification. Conventional fertilizers were considered vital for agricultural production to harvest high crop yields. Nevertheless, they are now deemed as environmentally hazardous and an obstacle to sustainable agroecosystems due to intensive chemical inputs that damage the soil over time and have long-lasting impacts. Conventional fertilization results in nutrient depletion, loss of microbial diversity, organic matter reduction, and deterioration of physical characteristics of the soil. Conversely, organic fertilization makes use of naturally existing resources to improve soil health. Organic amendments such as biochar, manure, and fermented grass improve soil’s physical, chemical, and biological properties and promote the growth and diversity of beneficial soil microorganisms—important in nutrient cycling and soil stability. They facilitate the uptake of nutrients, hinder crop pathogen growth, mitigate heavy metals, and decompose xenobiotic organic substances. Moreover, growing cover crops is also a major strategy to improve soil health. Diversified crop rotation with combinatorial use of organic fertilizers may improve soil health and agricultural yields without any detrimental impacts on the environment and soil, ensuring sustainable food production, safety, and security. This integrated approach contributes to minimizing the use of chemical fertilizers and their effects on environmental health. It also contributes to reducing agricultural inputs along with enhancing OM, soil microbial diversity and biomass, nitrogen fixation, and carbon sequestration. Therefore, cover crops and organic fertilization may offer sustainable agroecosystems and climate change mitigation.

Dual specific STAT3/5 degraders effectively block acute myeloid leukemia and natural killer/T cell lymphoma.

The transcription factors STAT3, STAT5A, and STAT5B steer hematopoiesis and immunity, but their enhanced expression and activation promote acute myeloid leukemia (AML) or natural killer/T cell lymphoma (NKCL). Current therapeutic strategies focus on blocking upstream tyrosine kinases to inhibit STAT3/5, but these kinase blockers are not selective against STAT3/5 activation and frequent resistance causes relapse, emphasizing the need for targeted drugs. We evaluated the efficacy of JPX-0700 and JPX-0750 as dual STAT3/5 binding inhibitors promoting protein degradation. JPX-0700/-0750 decreased the mRNA and protein levels of STAT3/5 targets involved in cancer survival, metabolism, and cell cycle progression, exhibiting nanomolar to low micromolar efficacy. They induced cell death and growth arrest in both AML/NKCL cell lines and primary AML patient blasts. We found that both AML/NKCL cells hijack STAT3/5 signaling through either upstream activating mutations in kinases, activating mutations in STAT3, mutational loss of negative STAT regulators, or genetic gains in anti-apoptotic, pro-proliferative, or epigenetic-modifying STAT3/5 targets. This emphasizes a vicious cycle for proliferation and survival through STAT3/5. Both JPX-0700/-0750 treatment reduced leukemic cell growth in human AML or NKCL xenograft mouse models significantly, being well tolerated by mice. Synergistic cell death was induced upon combinatorial use with approved chemotherapeutics in AML/NKCL cells.

Cooperative blockade of FLT3 and ALK synergistically suppresses growth of osteosarcoma.

Osteosarcoma is a common primary malignant bone tumor in children and young adults, with limited progress in improving survival rates for metastatic or recurrent cases. Kinase inhibitors have emerged as potential treatments for osteosarcoma due to the critical role kinases play in regulating cellular networks. However, single-agent kinase inhibitors often face challenges due to the activation of compensatory oncogenic signaling pathways, which can undermine treatment efficacy. In this study, a combination screening of FDA-approved kinase inhibitors was conducted in osteosarcoma cells. We identified the combination of ALK inhibitor and FLT3 inhibitor as a potent kinase-based therapeutic strategy for osteosarcoma. Our results showed that the combinatorial treatment synergistically suppressed osteosarcoma in cell lines, patient-derived organoids, and xenograft models. Mechanistically, the inhibition of FLT3 significantly promoted the activation of ALK, which subsequently enhanced its downstream PI3K/Akt and MAPK signaling pathways. The combinatorial use of an ALK inhibitor could reverse this process. Thus, our study demonstrates that the cooperative blockade of FLT3 and ALK synergistically suppresses osteosarcoma, providing a potential alternative for its treatment.

Comprehensive Insights Into the Combinatorial Uses of Selected Phytochemicals in Colorectal Cancer Prevention and Treatment: Isothiocyanates, Quinones, Carotenoids, and Alkaloids.

Despite the advancement in cancer diagnosis and treatment, colorectal cancer remains the leading cause of cancer-related death worldwide. Given the high recurrence rate of colorectal cancer even after surgical resection, chemotherapy has been clinically used to improve the treatment outcomes of colorectal cancer. However, chemotherapy is well-known for its toxic side effects. Thus, phytochemicals have been widely studied in recent years as preventive and therapeutic agents for colorectal cancer owing to their relatively low toxicity. Moreover, combinatorial uses of phytochemicals with other natural compounds or with drugs may amplify the positive outcomes of colorectal cancer prevention and treatment by intervening in multiple signaling pathways and targets. This review summarized the combinatorial use of several well-studied groups of phytochemicals, that is, isothiocyanates, quinones, carotenoids, and alkaloids, in the prevention and treatment of colorectal cancer, and suggested it as a potential approach to improve the anticancer efficacy of single compounds and minimize the toxic side effects associated with conventional drugs. Notably, we generalized the invitro, invivo, and clinical experiments-based molecular mechanisms whereby the selected phytochemicals in combination with other compounds exerted anti-colorectal cancer effects by inhibiting cancer cell proliferation, cell apoptosis, cell invasion, and tumor growth. Overall, this review provides a reference and new perspective to propel further advancements in research and development of preventative and therapeutic strategies for colorectal cancer.

HDAC6 as a Prognostic Factor and Druggable Target in HER2-Positive Breast Cancer.

Adjuvant trastuzumab is the standard of care for HER2+ breast cancer (BC) patients. However, >50% of patients become resistant. This study aimed at the identification of the molecular factors associated with disease relapse and their further investigation as therapeutically exploitable targets. Analyses were conducted on formalin-fixed paraffin-embedded tissues of the primary tumors of relapsed (cases) and not relapsed (controls) HER2+ BC patients treated with adjuvant trastuzumab. The nCounter Human Breast Cancer Panel 360 was used. Logistic regression and partitioning around medoids were employed to identify the genes associated with disease recurrence. Cytotoxicity experiments using trastuzumab-resistant cell lines and a network pharmacology approach were carried out to investigate drug efficacy. A total of 52 patients (26 relapsed and 26 not relapsed) were analyzed. We found that a higher expression of HDAC6 was significantly associated with an increased risk of recurrence, with an adjusted OR of 3.20 (95% CI 1.38-9.91, p = 0.016). Then, we investigated the cytotoxic activity of the selective HDAC6 inhibitor Nexturastat A (NextA) on HER2+ cell lines, which were both sensitive and trastuzumab-resistant. A sub-cytotoxic concentration of NextA, combined with trastuzumab, showed a synergistic effect on BC cell lines. Finally, using a network pharmacology approach, we identified HSP90AA1 as the putative molecular candidate responsible for the synergism observed in vitro. Our findings encourage the exploration of the role of HDAC6 as a prognostic factor and the combinatorial use of HDAC6 selective inhibitors combined with trastuzumab in HER2+ BC, in particular for those patients experiencing drug resistance.

Combination Immunotherapy With Radiotherapy in Non-Small Cell Lung Cancer: A Review of Evidence.

Radiotherapy plays a fundamental role in the treatment of patients with all stages of non-small-cell lung cancer (NSCLC). The emergence of immune checkpoint inhibitors (ICIs) has transformed the standard of care in these patients. The use of ICIs is increasingly utilized in the definitive setting as an adjunct to chemoradiotherapy or surgery and remains a vital component in the treatment of metastatic disease. Despite improvements in patient survival, the use of immunotherapy as monotherapy has shown limited overall response rates with susceptibility to resistance. Radiotherapy has been identified as a viable option to enhance the response rate to ICI and improve outcomes in NSCLC. We queried the English PubMed database utilizing variably combined search items including "radiation," "chemoradiation," "immune checkpoint," "immunotherapy," "stereotactic body radiotherapy," and "non-small-cell lung". We additionally searched various acceptable alternative terms for similar keywords such as "radiotherapy" in place of "radiation." These results were subsequently curated for relevance and impact on current treatment paradigms. In this review, we discuss preclinical and clinical studies relating to combinatorial use of immunotherapy and radiation in NSCLC. These studies are presented in the context of early-stage, operable stage III, unresectable stage III, and metastatic disease. The majority of the data illustrate promising results regarding the additive or synergistic effects of radiation and immunotherapy with a suggestion that the timing of these treatment modalities is crucial to optimizing outcomes. While there is now evidence regarding the favorable interplay between radiation and immunotherapy in NSCLC, there remain multiple unanswered questions which are expected to be addressed in ongoing clinical trials.

5-Fluorouracil induces apoptosis in nutritional deprived hepatocellular carcinoma through mitochondrial damage.

5-Fluorouracil (5-FU) is the leading chemotherapeutic drug used to treat hepatocellular carcinoma, one of the major cancer diseases after atherosclerosis. Because of chemo-resistance, the success rate of treatment declines with time due to continuous drug exposure. Though autophagy induction is majorly responsible for acquired resistance, the exact role of this evolutionary conserved mechanism is unknown in cancer cell survival and suppression. The usual practice involves the combinatorial use of chemotherapeutic drugs with autophagy inhibitors like Chloroquine and Bafilomycin A, while neglecting the side effects caused by autophagy impairment in healthy cells. Starvation is a well-known physiological inducer of autophagy. In this study, by caloric modulation, we tried to circumvent the resistance imposed by prolonged drug exposure and investigated the effect of 5-FU in nutrient-sufficient and deficient conditions. Our findings show a substantial correlation between autophagy and increased cancer cell death in the presence of 5-FU, with negligible effects on normal cells. Experimental data revealed that nutritional deprivation augmented cell death in the presence of 5-FU through mitochondrial membrane damage and excessive reactive oxygen species (ROS) production, initiating apoptosis. Lipidation study also unveiled that under such combinatorial treatment cellular metabolism shifts from glucose to lipid biosynthesis. Overall, our experimental findings suggest that nutritional deprivation in combination with chemotherapeutic medication can be a new effective strategy to control hepatocellular carcinoma.

Possible Combinatorial Utilization of Phytochemicals and Extracellular Vesicles for Wound Healing and Regeneration.

Organ and tissue damage can result from injury and disease. How to facilitate regeneration from damage has been a topic for centuries, and still, we are trying to find agents to use for treatments. Two groups of biological substances are known to facilitate wound healing. Phytochemicals with bioactive properties form one group. Many phytochemicals have anti-inflammatory effects and enhance wound healing. Recent studies have described their effects at the gene and protein expression levels, highlighting the receptors and signaling pathways involved. The extremely large number of phytochemicals and the multiple types of receptors they activate suggest a broad range of applicability for their clinical use. The hydrophobic nature of many phytochemicals and the difficulty with chemical stabilization have been a problem. Recent developments in biotechnology and nanotechnology methods are enabling researchers to overcome these problems. The other group of biological substances is extracellular vesicles (EVs), which are now known to have important biological functions, including the improvement of wound healing. The proteins and nanoparticles contained in mammalian EVs as well as the specificity of the targets of microRNAs included in the EVs are becoming clear. Plant-derived EVs have been found to contain phytochemicals. The overlap in the wound-healing capabilities of both phytochemicals and EVs and the differences in their nature suggest the possibility of a combinatorial use of the two groups, which may enhance their effects.

Efficient combinatorial adaptor-mediated targeting of acute myeloid leukemia with CAR T-cells

CAR T-cell products targeting lineage-specific cell-of-origin antigens, thereby eliminating both tumor and healthy counterpart cells, are currently clinically approved therapeutics in B- and plasma-cell malignancies. While they represent a major clinical improvement, they are still limited in terms of efficacy by e.g. single, sometimes low-expressed antigen targeting, and in terms of safety by e.g., lack of on-off activity. Successful cell-of-origin non-discriminative targeting of heterogeneous hematopoietic stem and progenitor cell malignancies, such as acute myeloid leukemia (AML), will require antigen-versatile targeting and off-switching of effectors in order to then allow rescue by hematopoietic stem cell transplantation (HSCT), preventing permanent myeloablation. To address this, we developed adaptor-CAR (AdFITC-CAR) T-cells targeting fluoresceinated AML antigen-binding diabody adaptors. This platform enables the use of adaptors matching the AML-antigen-expression profile and conditional activity modulation. Combining adaptors significantly improved lysis of AML cells in vitro. In therapeutic xenogeneic mouse models, AdFITC-CAR T-cells co-administered with single diabody adaptors were as efficient as direct CAR T-cells, and combinatorial use of adaptors further enhanced therapeutic efficacy against both, cell lines and primary AML. Collectively, this study provides proof-of-concept that AdFITC-CAR T-cells and combinations of adaptors can efficiently enhance immune-targeting of AML.

Individual and combinatorial application of nanosilica and carbon nanoparticles alleviate nickel stress in barley (Hordeum vulgare L.): Impacts on gene expression, AsA − GSH cycle, cellular fractionation, and proline metabolism

Individual and combinatorial application of nanosilica and carbon nanoparticles alleviate nickel stress in barley (Hordeum vulgare L.): Impacts on gene expression, AsA − GSH cycle, cellular fractionation, and proline metabolism

Engineering artificial cross-species promoters with different transcriptional strengths

Engineering artificial cross-species promoters with different transcriptional strengths

Aqueous Extracts of Ocimum gratissimum Sensitize Hepatocellular Carcinoma Cells to Cisplatin through BRCA1 Inhibition.

Ocimum gratissimum (O. gratissimum), a medicinal herb with antifungal and antiviral activities, has been found to prevent liver injury and liver fibrosis and induce apoptosis in hepatocellular carcinoma (HCC) cells. In this study, we evaluated the effect of aqueous extracts of O. gratissimum (OGE) on improving the efficacy of chemotherapeutic drugs in HCC cells. Proteomic identification and functional assays were used to uncover the critical molecules responsible for OGE-induced sensitization mechanisms. The antitumor activity of OGE in combination with a chemotherapeutic drug was evaluated in a mouse orthotopic tumor model, and serum biochemical tests were further utilized to validate liver function. OGE sensitized HCC cells to the chemotherapeutic drug cisplatin. Proteomic analysis and Western blotting validation revealed the sensitization effect of OGE, likely achieved through the inhibition of breast cancer type 1 susceptibility protein (BRCA1). Mechanically, OGE treatment resulted in BRCA1 protein instability and increased proteasomal degradation, thereby synergistically increasing cisplatin-induced DNA damage. Moreover, OGE effectively inhibited cell migration and invasion, modulated epithelial-to-mesenchymal transition (EMT), and impaired stemness properties in HCC cells. The combinatorial use of OGE enhanced the efficacy of cisplatin and potentially restored liver function in a mouse orthotopic tumor model. Our findings may provide an alternate approach to improving chemotherapy efficacy in HCC.