As the sixth most common cancer in the world, the development of gastric cancer (GC) is influenced by many factors. Recent studies have revealed a strong association between dyslipidaemia and GC. In this paper, the relationships between dyslipidaemia and GC are discussed in depth. We review the development of GC through the mechanisms of the inflammatory response, signalling pathways, and apolipoprotein function, and the intersecting targets of atherosclerosis and GC are explored. The synergistic effects of Helicobacter pylori infection and dyslipidaemia on the development of GC are also analysed, and the potential value of statins in the prevention and treatment of GC is discussed. In this review, we systematically investigated the relationship between dyslipidaemia and GC to provide new ideas for GC prevention and treatment.

Ferroptosis represents a distinctive and distinct form of regulated cellular death, which is driven by the accumulation of lipid peroxidation. It is distinguished by altered redox lipid metabolism and is linked to a spectrum of cellular activities, including cancer. In breast cancer (BC), with triple negative breast cancer (TNBC) being an iron-and lipid-rich tumor, inducing ferroptosis was thought to be a novel approach to killing breast tumor cells. However, in the recent past, a novel conceptual framework has emerged which posits that in addition to the promotion of tumor cell death, ferritin deposition has a potent immunosuppressive effect on the tumor immune microenvironment (TIME) via the influence on both innate and adaptive immune responses. TIME of BC includes various cell populations from both the innate and adaptive immune systems. In this review, the internal association between iron homeostasis and the progression of ferroptosis, along with the common inducers and protectors of ferroptosis in BC, are discussed in detail. Furthermore, a comprehensive analysis is conducted on the dual role of ferroptosis in immune cells and proto-oncogenic functions, along with an evaluation of the potential applications of immunogenic cell death-targeted immunotherapy in TIME of BC. It is anticipated that our review will inform future research endeavors that seek to integrate ferroptosis and immunotherapy in the management of BC.

Aberrant lipid metabolism is increasingly recognized as a hallmark of cancer, contributing to tumor growth, metastatic dissemination, and resistance to therapy. Cancer cells reprogram key metabolic pathways-including de novo lipogenesis, lipid uptake, and phospholipid remodeling-to sustain malignant progression and adapt to microenvironmental demands. This review summarizes current insights into the role of lipid metabolic reprogramming in oncogenesis and highlights recent advances in lipidomics that have revealed cancer type- and stage-specific lipid signatures with diagnostic and prognostic relevance. We emphasize the dual potential of lipid metabolic pathways-particularly those involving phospholipids-as sources of clinically relevant biomarkers and therapeutic targets. Enzymes and transporters involved in these pathways have emerged as promising candidates for both diagnostic applications and pharmacological intervention. We also examine persistent challenges hindering the clinical translation of lipid-based approaches, including analytical variability, insufficient biological validation, and the lack of standardized integration into clinical workflows. Furthermore, the review explores strategies to overcome these barriers, highlighting the importance of incorporating lipidomics into multi-omics frameworks, supported by advanced computational tools and AI-driven analytics, to decipher the complexity of tumor-associated metabolic networks. We discuss how such integrative approaches can facilitate the identification of actionable metabolic targets, improve the specificity and robustness of lipid-based biomarkers, and enhance patient stratification in the context of precision oncology.

Endometriosis is a gynecological disease characterized by the presence of endometrium-like cells located outside the uterus. The most widely accepted theory for endometriosis development, retrograde menstruation, does not account for extra-pelvic lesions or ones found on other organs in the peritoneal cavity. Similar to ovarian cancer, endometriosis cells can interact with the mesothelial cells of the peritoneal cavity. In ovarian cancer metastasis, ovarian cancer cell spheroids attach and push away the mesothelial cells lining the peritoneal cavity, clearing the mesothelial layer. Since endometriosis cells are known to interact with the mesothelium, we hypothesized that endometriosis cells would be able to form spheroids capable of undergoing mesothelial clearance. To test this, we designed an in vitro mesothelial clearance assay using endometriosis spheroids and a mesothelial cell monolayer. Our results demonstrate that normal and endometriotic epithelial cell spheroids can perform mesothelial clearance similar to ovarian cancer spheroids, though normal endometrial cells do not clear as well as endometriosis cells. Additionally, we demonstrated that our mesothelial clearance assay can test potential pharmacological therapies for endometriosis prior to clinical trials. These results give insight into the development of endometriosis lesions, but further research is needed to determine the mechanisms behind mesothelial clearance in endometriosis.

Statins have been appearing as a potential anti-cancer agent in numerous studies. The study aimed to unravel the impact of statins in pancreatic cancer in terms of reducing the occurrence (morbidity) and improving survival (mortality).

A comprehensive search of databases was carried out to collect the eligible studies up to July 2024. This meta-analysis evaluates two distinct questions: (1) whether statin use reduces the incidence of pancreatic ductal adenocarcinoma (PDAC) in the general population, and (2) whether statins improve survival among patients diagnosed with PDAC. In total, 39 studies were included in the meta-analysis, comprising 15 case-control studies, 20 cohort studies, three randomized controlled trials, and one non-randomized controlled trial. A generic inverse variance weighted random-effects model was applied to calculate the pooled risk ratio and 95% confidence intervals. Subgroup analyses were performed based on the availability of relevant information.

In the total meta-analysis, aggregated results demonstrated a substantial decrease in pancreatic cancer risk in all statin users (RR 0.94; 95% CIs, 0.90-0.97, and p-value = 0.0008). The pooled risk ratio estimate of lipophilic statins was 0.97 (95% CI, 0.87-1.07; P = 0.50; I2 = 0.0%). The estimated pooled risk ratios of long-term and short-term statin use were 0.80 (95% CI, 0.69-0.92; P = 0.002; I2 = 42%) and 0.86 (95% CI, 0.70-1.06; P = 0.15; I2 = 96%), respectively. For long-term and short-term follow-up, the risk ratios were 0.81 (95% CI, 0.70-0.94; P = 0.007; I2 = 55%) and 0.96 (95% CI, 0.90-1.02; P = 0.16; I2 = 26%), respectively. As for the studies collectively, heterogeneity was tested using the Cochrane chi square test (p-value = = 0.40, I2 = 4%). No publication bias was found.

The overall outcome of the study indicates that statins might lower the occurrence and increase the survival of PDAC patients.

Patients with end-stage renal disease (ESRD) are predisposed to a higher risk of developing malignancies. This study aimed to explore the association between chronic dialysis with ESRD treated and the subsequent development of urothelial cell carcinoma or renal cell carcinoma (UC/RCC). Data spanning 13 years were retrieved from Taiwan's National Health Insurance Research Database. A total of 11,820 patients with ESRD undergoing maintenance dialysis between January 1, 2000, and December 31, 2013, and 35,460 controls matched for sex, age, and index year, were identified. After adjusting for confounding factors, Cox proportional hazards analysis was performed to compare the risk of UC/RCC during the 13-year follow-up period, and Kaplan-Meier analysis was used to evaluate the cumulative UC/RCC incidence between the ESRD and non-ESRD cohorts. The average time before developing UC/RCC was 4.18 years after dialysis initiation in the ESRD group compared to 5.39 years in the control group. After adjusting for sex, age, monthly income, urbanization level, geographic region, and comorbidities, the hazard ratio for UC/RCC was 1.186 (95% confidence interval, 1.071-1.448; P = .005). Stratified by age, the odds ratios (ORs) for developing UC/RCC were 2.105, 1.498, 1.371, and 0.925 among patients with ESRD aged 40 to 49, 50 to 59, 60 to 69, and ≥ 70 years, respectively. Stratification by comorbidities revealed ORs of 1.204, 1.179, 1.186,1.172, 1.211, and 1.210 for patients without diabetes mellitus, hyperlipidemia, obesity, coronary artery disease, chronic obstructive pulmonary disease, and hematuria, respectively. The mean time to UC/RCC occurrence was 4.18 years after dialysis. Furthermore, younger male patients undergoing dialysis with fewer comorbidities were at higher risk of developing UC/RCC. Early or more intensive surveillance for urological cancers post-dialysis initiation is recommended for patients undergoing dialysis with longer life expectancies or a higher likelihood of undergoing renal transplantation.

Statins, widely recognized as a cornerstone in the prevention of cardiovascular diseases, have garnered increasing attention in oncology due to their pleiotropic effects, particularly their potential roles in regulating breast and colorectal cancer. Emerging evidence suggests that statins may exert anticancer effects through multiple mechanisms, including the mitochondrial apoptosis pathway, the LKB1-AMPK-p38MAPK-p53-survivin signaling cascade, inhibition of the mevalonate pathway, modulation of the EGFR/RhoA and IGF-1 signaling pathways, and regulation of the BMP/SMAD4 signaling pathway. However, significant heterogeneity exists in the reported anticancer effects of statins, likely due to variations in statin type (lipophilic vs hydrophilic), dosage, treatment duration, and population-specific characteristics. These factors contribute to inconsistencies in study outcomes. Additionally, while combination therapies incorporating statins with chemotherapy and immunotherapy have demonstrated synergistic effects in certain studies, their clinical utility remains to be fully established. Nevertheless, current evidence suggests that statins may have a potential role in reducing breast and colorectal cancer-related mortality. Future research should prioritize elucidating their precise molecular mechanisms, defining dose-response relationships, developing personalized treatment strategies within the framework of precision medicine, and validating their efficacy through large-scale, long-term prospective studies. These efforts will provide a more robust scientific foundation for the clinical application of statins in oncology. This review systematically explores the role of statins in breast and colorectal cancer regulation, covering clinical evidence, underlying biological mechanisms, pharmacological distinctions, synergistic therapeutic potential, and translational medicine prospects.

Glioblastoma (GBM) is an aggressive primary brain tumor with high lethality. The typical treatment regimen includes post-surgical radiotherapy and temozolomide (TMZ) chemotherapy, which helps extend survival. Nevertheless, TMZ resistance occurs in approximately 50% of patients. This resistance is primarily associated with the expression of O6-methylguanine-DNA methyltransferase (MGMT), which repairs O6-methylguanine lesions generated by TMZ and is thought to be the major mechanism of drug resistance. Additionally, the mismatch repair and base excision repair pathways play crucial roles in TMZ resistance. Emerging studies also point to drug transport mechanisms, glioma stem cells, and the heterogeneous tumor microenvironment as additional influences on TMZ resistance in gliomas. A better understanding of these mechanisms is vital for developing new treatments to improve TMZ effectiveness, such as DNA repair inhibitors, inhibitors of multidrug transporting proteins, TMZ analogs, and combination therapies targeting multiple pathways. This article discusses the main resistance mechanisms and potential strategies to counteract resistance in GBM patients, aiming to broaden the understanding of these mechanisms for future research and to explore the therapeutic effects of traditional Chinese medicines and their active components in overcoming TMZ resistance.

Head and neck cancer (HNC) encompasses a heterogeneous group of malignancies originating in the oral cavity, pharynx, nasopharynx, larynx, paranasal sinuses, and salivary glands. Accumulating evidence indicates that metabolic syndrome (MetS) characterized by a constellation of conditions including central adiposity, hyperglycemia, dyslipidemia, hypertension, and insulin resistance, may significantly influence cancer pathogenesis and progression.

MetS has been epidemiologically linked to elevated risk for multiple malignancies through various metabolic mechanisms involving chronic systemic inflammation, insulin resistance, and dysregulated lipid metabolism. Especially in HNC, recent studies demonstrated that MetS and metabolic imbalance conditions may contribute to carcinogenesis, disease progression, and clinical outcomes, but the exact mechanisms behind the association between excess fat accumulation and HNC risk remain unclear. Considering previous studies, pharmacological agents targeting metabolic pathways, including biguanides (metformin), thiazolidinediones, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, and HMG-CoA reductase inhibitors (statins) are being investigated for potential repurposing in cancer prevention and adjuvant therapy.

Here, we summarize the latest evidence on the relationship between MetS and HNC, highlighting the therapeutic potential of anti-diabetes drugs and anti-dyslipidemia drugs in ameliorating various pathological problems in HNC patients with MetS.

Fatty acid-binding proteins (FABPs) act as lipid chaperones and play a role in the pathological processes of various lipid signaling pathways. Mitochondria are crucial for the regulation of lipid metabolism. As an aging marker, lipid-mediated mitochondrial dysfunction has been observed in the etiology of numerous diseases, including neurodegenerative diseases, metabolic syndromes, cardiovascular diseases, and tumorigenesis. Members of the FABP family have been identified to regulate mitochondrial function. Targeting FABPs specifically may provide a promising approach to improve mitochondrial function and treat age-related diseases. This review summarizes the connection between FABPs and mitochondrial function and highlights certain FABPs involved in age-related diseases that hold significant therapeutic promise.

Scavenger receptor class B type 1 (SR-B1) is a cholesterol transporter, abundantly expressed in human melanoma, yet its precise role for melanoma progression is not fully understood. This study investigates the involvement of SR-B1 in cholesterol homeostasis of tumor cells and its implications for potential therapy. We found that SR-B1 depletion in melanoma cells does not alter total cholesterol levels, but induces cholesterol biosynthesis. This effect was characterized by an increased expression of HMG-CoA reductase (HMGCR), a rate limiting enzyme of cholesterol biosynthesis. Notably, further analyses indicated that this regulation occurs at the post-translational level, mediated via the hypoxia-inducible factor (HIF) signaling pathway. Importantly, we identified SR-B1 as a transporter of the lipid hormone sphingosine-1-phosphate (S1P) and we found that S1P exposure leads to HIF1A up-regulation. Finally, we used a pluripotent stem cell-derived skin organoid model to show that targeting SR-B1 in combination with targeted melanoma therapy can lead to increased apoptosis and suppressed proliferation of transplanted tumor cells. Our study shows that functional SR-B1 is linked to inflammatory signaling, which reduces cholesterol synthesis, while enabling melanoma cell survival during chemotherapy treatment.

Pediatric solid tumors represent a significant subset of childhood cancers, accounting for approximately 60% of new diagnoses. Despite advancements in therapeutic strategies, survival rates remain markedly disparate between high-income and resource-limited settings, underscoring the urgent need for novel and effective treatments. Lipid metabolic reprogramming is a fundamental hallmark of cancer, driving tumor progression, therapeutic resistance, and immune evasion through enhanced fatty acid uptake, increased de novo lipid synthesis, and activated fatty acid β-oxidation (FAO). Ubiquitination, a dynamic post-translational modification mediated by the ubiquitin-proteasome system (UPS), plays a crucial role in regulating lipid metabolism by modulating the stability and activity of key metabolic enzymes and transporters involved in cholesterol and fatty acid pathways. This review comprehensively examines the complex interplay between ubiquitination and lipid metabolic reprogramming in pediatric solid tumors. It delineates the mechanisms by which ubiquitination influences cholesterol biosynthesis, uptake, efflux, and fatty acid synthesis and oxidation, thereby facilitating tumor growth and survival. Furthermore, the review identifies potential UPS-mediated therapeutic targets and explores the feasibility of integrating ubiquitination-based strategies with existing treatments. By targeting the UPS to disrupt lipid metabolism pathways, novel therapeutic avenues may emerge to enhance treatment efficacy and overcome resistance in pediatric oncology. This synthesis of current knowledge aims to provide a foundation for the development of innovative, precision medicine approaches to improve clinical outcomes for children afflicted with solid tumors.

Cancer, uncontrolled cell growth due to the loss of cell cycle regulation, is often found to be associated with viral infections and, as recent studies show, with bacterial infections as well. Emerging reports also suggest a strong link between fungi and cancer. The crucial virulence trait of fungi, the switch from yeast (Y) to hyphal (H) form, is found to be associated with carcinogenesis. The physicochemical properties and signal transduction pathways involved in the switch to the hyphal form overlap with those of tumor cell formation. Inhibiting differentiation causes apoptosis in fungi, whereas preventing apoptosis leads to cancer in multicellular organisms. Literature on the fungi-cancer linkage, though limited, is increasing rapidly. This review examines cancer-specific fungal communities, the impact of fungal microbiome on cancer cell progression, similarities between fungal differentiation and cells turning cancerous at biochemical and molecular levels, including the overlaps in signal transduction pathways between fungi and cancer. Based on the available evidence, we suggest that molecules inhibiting the yeast-hyphal transition in fungi can be combined with those targeting tumor cell apoptosis for effective cancer treatment. The review points out fertile research areas where mycologists and cancer researchers can collaborate to unravel common molecular mechanisms. Moreover, antibodies targeting fungal-specific chitin and glucan can be used for the selective neutralization of tumor cells. These new combinations of potential therapies are expected to facilitate the development of target-specific, less harmful and commercially feasible anticancer therapies. We bring together available evidence to argue that fungal infections could either trigger cancer or have a significant role in the development and progression of cancer. Hence, cancer-associated fungal populations could be utilized as a target for a combination therapy involving the integration of anticancer and antifungal drugs as well as inhibitors of fungal morphogenesis to develop more effective anticancer therapies.

Acute Myeloid Leukemia (AML) is characterized by aggressive proliferation and metabolic reprogramming that support its survival and resistance to therapy. This review explores the metabolic distinctions between AML cells and normal hematopoietic stem cells (HSCs), emphasizing the role of altered mitochondrial function, oxidative phosphorylation (OXPHOS), and biosynthetic pathways in leukemic progression. AML cells exhibit distinct metabolic vulnerabilities, including increased mitochondrial biogenesis, reliance on glycolysis and amino acid metabolism, and unique signaling interactions that sustain leukemic stem cells (LSCs). These dependencies provide potential therapeutic targets, as metabolic inhibitors have demonstrated efficacy in disrupting AML cell survival while sparing normal hematopoietic cells. We examine current and emerging metabolic therapies, such as inhibitors targeting glycolysis, amino acid metabolism, and lipid biosynthesis, highlighting their potential in overcoming drug resistance. However, challenges remain in translating these strategies into clinical practice due to AML's heterogeneity and adaptability. Further research into AML's metabolic plasticity and precision medicine approaches is crucial for improving treatment outcomes. Understanding and exploiting AML's metabolic vulnerabilities could pave the way for novel, more effective therapeutic strategies.

Statins, hydroxymethylglutaryl-CoA reductase inhibitors, possess neuroprotective properties. Given the potential neuroprotective properties of statins and their prevalent use in clinical settings, we aimed to investigate their impact on chemotherapy-induced peripheral neuropathy (CIPN) in Japan by assessing both their safety and efficacy in this context.

We conducted a retrospective observational study using the Japan Medical Data Centre database, which includes data from 2005 to 2021. We included patients who underwent anticancer therapy and were categorized into non-statin (10,920) and statin (1,537) groups. These groups were matched using a propensity score, resulting in 2,548 non-statin and 1,274 statin users. The primary endpoints were the incidence of CIPN post-first prescription of each anticancer drug and overall survival.

Treatment with statins did not increase the incidence of CIPN (non-statin 27.2% vs. statin 28.4%, P = 0.443). Nevertheless, the incidence of CIPN was significantly high among women (non-statin 28.0% vs. statin 33.2%, P = 0.025). Overall survival was not impacted by statin use (hazard ratio 0.98, 95%CI: 0.83-1.16, P = 0.8846). Among men treated with paclitaxel, we observed an improvement in overall survival (hazard ratio: 0.72; 95% CI: 0.56-0.92; P = 0.0110).

The use of statins in patients with cancer was not associated with CIPN incidence. However, in men receiving paclitaxel treatment, statins may be linked to improved overall survival. Further studies are necessary to clarify the factors influencing prognosis and CIPN severity.

Within the tumor microenvironment, tumor cells undergo metabolic reprogramming of cholesterol due to intrinsic cellular alterations and changes in the extracellular milieu. Furthermore, cholesterol reprogramming within this microenvironment influences the immune landscape of tumors, facilitating immune evasion and consequently promoting tumorigenesis. These biological changes involve modifications in numerous enzymes associated with cholesterol uptake and synthesis, including NPC1L1, SREBP, HMGCR, SQLE, and PCSK9.

This review systematically summarizes the role of cholesterol metabolism and its associated enzymes in cancer progression, examines the mechanisms through which dysregulation of cholesterol metabolism affects immune cells within the tumor microenvironment, and discusses recent advancements in cancer therapies that target cholesterol metabolism.

Targeting cholesterol metabolism-related enzymes can inhibit tumor growth, reshape immune landscapes, and rejuvenate antitumor immunity, offering potential therapeutic avenues in cancer treatment.

Colorectal cancer (CRC) is a growing health concern globally and in regions such as the United Arab Emirates, where risk factors like obesity and hyperlipidaemia are prevalent. Chronic inflammation, driven by pathways involving protease-activated receptor 2 (PAR-2), plays a pivotal role in CRC progression, creating a tumour-promoting microenvironment. The overexpression of PAR-2 has been associated with increased tumour aggressiveness and drug resistance. While previous studies have focused on broad inflammatory modulation, this study explores the selective targeting of PAR-2 by atorvastatin (ATV) and rosuvastatin (RSV), highlighting their specificity by assessing minimal impact on PAR-1 expression, which serves as a control.

HT-29 and Caco-2 CRC cell lines were employed to investigate the anti-inflammatory effects of ATV and RSV. Inflammation was induced with lipopolysaccharide (LPS), followed by treatment with varying concentrations of ATV and RSV. Western blotting and real-time polymerase chain reaction for quantification (qPCR) were performed to quantify PAR-2 and TNF-α at both the protein and mRNA levels. Enzyme linked immunosorbent assay (ELISA) was used to measure the secretion of TNF-α. Calcium signalling, which plays a crucial role in inflammation, was analysed using Fluo-4 AM dye, with fluorescence imaging capturing the effects of statin treatment on intracellular calcium influx.

LPS treatment significantly upregulated PAR-2 and TNF-α expression in both cell lines, validating the inflammatory model. Co-treatment with ATV or RSV reduced PAR-2 and TNF-α expression in a dose-dependent manner. The higher concentrations of ATV (50 µg/mL) and RSV (20 µg/mL) produced the most significant reduction in these inflammatory markers at both the protein and mRNA levels. Importantly, the treatment did not substantially alter PAR-1 expression, underlining the specificity of ATV and RSV in modulating PAR-2-mediated pathways. Additionally, statin treatment attenuated LPS-induced calcium influx, with fluorescence intensity decreasing markedly at higher concentrations of both statins.

This study provides novel insights into the selective targeting of PAR-2 by ATV and RSV, distinguishing their effects from PAR-1. The reduction in PAR-2 expression and TNF-α secretion, along with the suppression of calcium signalling, underscores the potential of these statins as targeted anti-inflammatory agents in CRC. The findings highlight the therapeutic value of ATV and RSV in modulating inflammation through PAR-2-specific pathways, which may contribute to reduced cancer progression. These results pave the way for further preclinical and clinical evaluations to explore statins as adjunctive therapies in the management of CRC.

The treatment of gastric cancer remains challenging, with immunotherapy serving as a critical component of the holistic approach to its treatment. The results of this study indicated that statins could decrease the serum levels of interleukin-enhancing binding factor 3 (ILF3) and programmed cell death ligand 1(PD-L1) in GC patients and improve their prognosis. Functional experiments demonstrated that simvastatin induced ferroptosis by inhibiting ILF3 in GC cells and enhanced the killing effect of activated CD8+ T cells on GC cells. The CUT&Tag assay revealed that, mechanistically, simvastatin inhibited ILF3 expression by reducing the acetylation level at residue site H3K14 in ILF3. Next-generation sequencing and Kyoto Encyclopedia of Genes and Genomes analysis revealed that ILF3 regulated PD-L1 expression through the DEPTOR/mTOR signaling pathway. Overall, simvastatin induced ferroptosis in GC cells by inhibiting ILF3 expression while promoting the activation of CD8+ T cells to augment antitumor immune responses, thereby facilitating synergistic immunotherapy.

The nervous system plays a critical role in developmental biology and oncology, influencing processes from ontogeny to the complex dynamics of cancer progression. Interactions between the nervous system and cancer significantly affect oncogenesis, tumor growth, invasion, metastasis, treatment resistance, inflammation that promotes tumors, and the immune response. A comprehensive understanding of the signal transduction pathways involved in cancer biology is essential for devising effective anti-cancer strategies and overcoming resistance to existing therapies. Recent advances in cancer neuroscience promise to establish a new cornerstone of cancer therapy. Repurposing drugs originally developed for modulating nerve signal transduction represent a promising approach to target oncogenic signaling pathways in cancer treatment. This review endeavors to investigate the potential of repurposing neurological drugs, which target neurotransmitters and neural pathways, for oncological applications. In this context, it aims to bridge the interdisciplinary gap between neurology, psychiatry, internal medicine, and oncology. By leveraging already approved drugs, researchers can utilize existing extensive safety and efficacy data, thereby reducing both the time and financial resources necessary for the development of new cancer therapies. This strategy not only promises to enhance patient outcomes but also to expand the array of available treatments, thereby enriching the therapeutic landscape in oncology.

Cholesterol is a crucial structural component of cell membranes, playing a vital role in maintaining membrane fluidity and stability. Cholesterol metabolism involves four interconnected processes: de novo synthesis, uptake, efflux, and esterification. Disruptions in any of these pathways can lead to imbalances in cholesterol homeostasis, which are significantly associated with cancer progression. In recent years, traditional Chinese medicine (TCM) has emerged as a comprehensive therapeutic approach with multi-target and multi-pathway effects, demonstrating significant potential in regulating cholesterol metabolism. Research has shown that certain components of TCM can modulate enzymes, transport proteins, and signaling pathways involved in cholesterol metabolism, effectively interfering with survival and migration of cancer. These mechanisms highlight the unique advantages of TCM in inhibiting tumor progression. In this review we systematically describe the execution and regulation of the four key cholesterol metabolism processes, highlights the roles of critical proteins involved, and provides a comprehensive overview of natural products from TCM that modulate cholesterol metabolism. This review provides valuable insights for the development of novel drugs and cancer therapeutic strategies targeting cholesterol metabolism.

This study aimed to evaluate the effects of antihypertensives, lipid-lowering agents, and antiplatelet medications on hepatocellular carcinoma (HCC) risk in patients with fatty liver disease (FLD) and type 2 diabetes (T2D).

Using data from Korea Health Insurance Review and Assessment Service, 212,443 FLD-T2D patients were analyzed through Cox regression, propensity score matching (PSM), and Kaplan-Meier analysis. The analysis considered medication use and its relation to HCC development. Cohort admission day was set as the date of the first oral hypoglycemic prescription.

The multivariate Cox regression analysis revealed that old age, male sex, chronic viral hepatitis, alcoholic liver disease, liver cirrhosis, using a combination of insulin and oral hypoglycemic agents for antidiabetic treatment, and calcium channel blocker (CCB) use were significantly correlated with higher HCC development risk, whereas dyslipidemia and statin, ezetimibe, and fibrate use was correlated with lower HCC risk, in the study cohort of 212,443 patients. Patients who used statins (hazard ratio [HR] = 0.58, 95% confidence interval [CI] = 0.42-0.80, P = 0.001) and fibrates (HR = 0.46, 95% CI = 0.22-0.93, P = 0.031) showed a significantly lower risk of HCC development even after PSM. In contrast, CCB use was linked to an elevated HCC risk (HR = 1.35, 95% CI = 1.05-1.72, P = 0.019), highlighting the differential impact of various medications on HCC incidence.

The use of specific medications, such as statins and fibrates, may offer protective effects against HCC in patients with FLD-T2D, whereas that of CCB may increase the risk. This underscores the importance of tailored medication strategies for the management of chronic conditions.

Statins have been shown to improve the possibility of a pathological complete response (pCR) in patients with locally advanced rectal cancer when given in combination with neo-adjuvant chemo-radiation (NACTRT) in observational studies. The primary objective of this phase II randomized controlled trial (RCT) is to determine the impact of rosuvastatin in improving pCR rates in patients with locally advanced rectal cancer who are undergoing NACTRT. The secondary objectives are to compare adverse events, postoperative morbidity and mortality, disease-free survival (DFS), and overall survival in the two arms and to identify potential prognostic and predictive factors determining outcomes. If the study is positive, we plan to proceed to a phase III RCT with 3-year DFS as the primary endpoint.

This is a prospective, randomized, open-label phase II/III study. The phase II study has a sample size of 316 patients (158 in each arm) to be accrued over 3 years to have 288 evaluable patients. The standard arm will receive NACTRT while the intervention group will receive 20 mg rosuvastatin orally once daily along with NACTRT for 6 weeks followed by rosuvastatin alone for 6-10 weeks until surgery. All patients will be reviewed after repeat imaging by a multidisciplinary tumor board at 12-16 weeks after starting NACTRT and operable patients will be planned for surgery. The pathological response rate, tumor regression grade (TRG), and post-surgical complications will be recorded.

The addition of rosuvastatin to NACTRT may improve the oncological outcomes by increasing the likelihood of pCR in patients with locally advanced rectal cancer undergoing NACTRT. This would be a low-cost, low-risk intervention that could potentially lead to the refinement of strategies, such as "watch and wait", in a select subgroup of patients.

Clinical Trials Registry of India, identifier CTRI/2018/11/016459.

Prostate cancer (PCA) is the second most widespread cancer among men globally, with a rising mortality rate. Enzyme-responsive lipid nanoparticles (ERLNs) are promising vectors for the selective delivery of anticancer agents to tumor cells. The goal of this study is to fabricate ERLNs for dual delivery of gefitinib (GF) and simvastatin (SV) to PCA cells.

ERLNs loaded with GF and SV (ERLNGFSV) were assembled using bottom-up and top-down techniques. Subsequently, these ERLN cargoes were coated with triacylglycerol, and phospholipids and capped with chitosan (CS). The ERLNGFSV, and CS engineered ERLNGFSV (CERLNGFSV) formulations were characterized for particle size (PS), zeta potential (ZP), and polydispersity index (PDI). The biocompatibility, and cytotoxicity of the plain and GF plus SV-loaded ERLN cargoes were assessed using erythrocytes and PC-3 cell line. Additionally, molecular docking simulations (MDS) were conducted to examine the influence of GF and SV on succinate dehydrogenase (SDH), glutathione peroxidase-4 (GPX-4), and 5α-reductase (5α-RD).

These results showed that plain, ERLNGFSV, and CERLNGFSV cargoes have a nanoscale size and homogeneous appearance. Moreover, ERLNGFSV and CERLNGFSV were biocompatible, with no detrimental effects on erythrocytes. Treatment with GF, SV, GF plus SV, ERLNGFSV, and CERLNGFSV significantly reduced the viability of PC-3 cells compared to control cells. Particularly, the blend of GF and SV, as well as ERLNGFSV and CERLNGFSV augmented PC-3 cell death. Also, treating PC-3 cells with free drugs, their combination, ERLNGFSV, and CERLNGFSV formulations elevated the percentage of apoptotic cells. MDS studies demonstrated that GF and SV interact with the active sites of SDH, GPX-4, and 5α-reductase.

This study concludes that SVGF combination and ERLNs loading induce particular delivery, and synergism on PC-3 death through action on multiple pathways involved in cell proliferation, and apoptosis, besides the interaction with SDH, GPX-4, and 5α-RD. Therefore, GFSV-loaded ERLN cargoes are a promising strategy for PCA treatment. In vivo studies are necessary to confirm these findings for clinical applications.

Among the most common malignant tumors, hepatocellular carcinoma (HCC) is a primary liver cancer type that has a high mortality rate. HCC often presents insidiously, is prone to recurrence, and has limited treatment efficacy. Ferroptosis regulates tumorigenesis, progression, and metastasis, which is a novel form of iron-dependent cell death. Numerous studies suggest that HCC is sensitive to ferroptosis, indicating that targeted therapies aimed at inducing ferroptosis may represent a promising new approach to cancer treatment. This study aims to find genes associated with HCC and ferroptosis, as well as to screen for potential agents that may cause ferroptosis in HCC. Transcriptome and clinical sample data were obtained from the TCGA database to identify differentially expressed genes related to ferroptosis. Using various regression and survival analysis techniques, we developed a prognostic model based on four core genes and evaluated its predictive potential. Subsequently, we screened for potential therapeutic agents in the Connective Map (CMap) database, designated as compound Atorvastatin, based on differential genes from two risk groups and related to ferroptosis. Through experiments conducted in vivo and in vitro, we demonstrated that Atorvastatin can induce ferroptosis in HCC cells while inhibiting their growth and migration. In conclusion, this research targets ferroptosis therapy and provides new insights for improving the prediction and prevention of HCC.

Over the past century, the chick embryo model, historically employed for research in developmental biology, has become a valuable tool for cancer research. The characteristics of the chick chorioallantoic membrane (CAM) make it a convenient model for the study of cancer, leading to the establishment of the CAM assay as an alternative to traditional in vivo cancer models. In this review we will explore the characteristics of the CAM that make it suitable for cancer research, as well as its consolidation as a versatile platform in this field. We will put particular emphasis on describing the key features that make this model an important asset for studying the hallmarks of cancer and for testing a wide variety of therapeutic strategies for its treatment, and which make it a suitable host for patient-derived xenografts (PDX). Additionally, we will examine the wide spectrum of methodological approaches available to study these subjects, highlighting some innovative cases. Finally, we will discuss the advantages and disadvantages of the chick CAM as a model for cancer research and how we can improve this model to its full potential.

Pancreatic cancer remains one of the most lethal cancers due to late diagnosis and high chemoresistance. Despite recent progression in the development of chemotherapies, immunotherapies, and potential nanoparticles-based approaches, the success rate of therapeutic response is limited which is further compounded by cancer drug resistance. Understanding of emerging biological and molecular pathways causative of pancreatic cancer's aggressive and chemoresistance is vital to improve the effectiveness of existing therapeutics and to develop new therapies. One such under-investigated and relatively less explored area of research is documenting the effect that lipids, specifically cholesterol, and its metabolism, impose on pancreatic cancer. Dysregulated cholesterol metabolism has a profound role in supporting cellular proliferation, survival, and promoting chemoresistance and this has been well established in various other cancers. Thus, we aimed to provide an in-depth review focusing on the significance of cholesterol metabolism in pancreatic cancer and relevant genes at play, molecular processes contributing to cellular cholesterol homeostasis, and current research efforts to develop new cholesterol-targeting therapeutics. We highlight the caveats, weigh in different experimental therapeutic strategies, and provide possible suggestions for future research highlighting cholesterol's importance as a therapeutic target against pancreatic cancer resistance and cancer progression.

previous studies have indicated that influenza vaccination may be associated with reduced risks of certain types of cancer. However, the protective effect of influenza vaccination against primary liver cancer in individuals with hypertension remains unclear.

In this cohort study, 37,022 patients over 55 years of age who received a diagnosis of hypertension at any time between January 1, 2001, and December 31, 2012, were enrolled from the National Health Insurance Research Database. The patients were divided into a vaccinated and an unvaccinated group. Categorical and continuous variables were analyzed using the chi-square test and t test, respectively, and the correlation between influenza vaccination and liver cancer in patients with hypertension was analyzed using time-varying COX model. Propensity score method was performed to reduce selection bias.

Compared with the unvaccinated group, the vaccinated group had a significantly lower incidence of liver cancer (hazard ratio = 0.56, 95% confidence interval = 0.46-0.64; p < .001). In addition, a protective effect was observed regardless of sex, age, or comorbidities. Besides, the association was dose-dependent which could be noted when patients were stratified based on the total number of vaccinations. The adjusted HRs for patients receiving 1, 2 to 3, and ≥ 4 vaccinations during the follow-up period were 0.60 (0.51-0.78), 0.48 (0.38-0.65), and 0.39(0.30-0.51), respectively.

In summary, influenza vaccination is linked to a decreased risk of liver cancer in individuals with hypertension. However, unmeasurable confounders may have been present in the analysis.

Growth differentiation factor 15 (GDF15) is upregulated in most cases of epithelial ovarian cancer (EOC); however, its functions in EOC are not fully understood. In this study, we knocked down GDF15 in EOC cells before performing high-throughput sequencing to identify genes regulated by GDF15. GDF15 was overexpressed to determine its effect on the viability, migration, and response of EOC cells to gemcitabine, carboplatin, and paclitaxel. Reprogramming of glucose and cholesterol metabolism in EOC cells was evaluated based on oxygen consumption, lactic acid production, complex I activity, and free and esterified cholesterol levels. The activities of ATP-binding cassette (ABC)B1 and ABCC1 were assessed based on the expulsion efficiency of rhodamine 12. GDF15 overexpression promoted cell viability, migration, and resistance to gemcitabine. In addition, GDF15 induced glycolysis and increased cholesterol levels in EOC cells. Cholesterol metabolism regulated by GDF15 contributed to the resistance of EOC cells to gemcitabine by elevating ABCB1 and ABCC1 levels in lipid rafts. DHCR24 plays an important role in cholesterol synthesis. DHCR24 was identified as a downstream effector of GDF15, because knockdown of DHCR24, but not treatment with statins, suppressed the cancer-promoting effect of GDF15. Overall, GDF15 promoted the resistance of EOC cells to gemcitabine via DHCR24-mediated cholesterol metabolism to elevate ABCB1 and ABCC1 levels in lipid rafts. Therefore, GDF15 and DHCR24 are potential therapeutic targets for suppressing the growth of EOC cells and improving their sensitivity to gemcitabine.

Skin cancer represents a major health concern due to its rising incidence and limited treatment options. Current treatments (surgery, chemotherapy, radiotherapy, immunotherapy, and targeted therapy) often entail high costs, patient inconvenience, significant adverse effects, and limited therapeutic efficacy. The search for novel treatment options is also marked by the high capital investment and extensive development involved in the drug discovery process. In response to these challenges, repurposing existing drugs for topical application and optimizing their delivery through nanotechnology could be the answer. This innovative strategy aims to combine the advantages of the known pharmacological background of commonly used drugs to expedite therapeutic development, with nanosystem-based formulations, which among other advantages allow for improved skin permeation and retention and overall higher therapeutic efficacy and safety. The present review provides a critical analysis of repurposed drugs such as doxycycline, itraconazole, niclosamide, simvastatin, leflunomide, metformin, and celecoxib, formulated into different nanosystems, namely, nanoemulsions and nanoemulgels, nanodispersions, solid lipid nanoparticles, nanostructured lipid carriers, polymeric nanoparticles, hybrid lipid-polymer nanoparticles, hybrid electrospun nanofibrous scaffolds, liposomes and liposomal gels, ethosomes and ethosomal gels, and aspasomes, for improved outcomes in the battle against skin cancer. Enhanced antitumor effects on melanoma and nonmelanoma research models are highlighted, with some nanoparticles even showing intrinsic anticancer properties, leading to synergistic effects. The explored research findings highly evidence the potential of these approaches to complement the currently available therapeutic strategies in the hope that these treatments might one day reach the pharmaceutical market.

Background/Objectives: Drug repurposing explores new applications for approved medications, such as simvastatin (SV), a lipid-lowering drug that has shown anticancer potential but is limited by solubility and side effects. This study aims to enhance SV delivery and efficacy against lung cancer cells using bioactive lipid nanoparticles formulated with plant-derived monoterpenes as both nanostructuring agents and anticancer molecules. Methods: Lipid nanoparticles were produced by ultrasonication and characterized for morphology, size, zeta potential, and polydispersity index (PDI). Monoterpenes (linalool-LN-, limonene, 1,8-cineole) or Crodamol® were used as liquid lipids. Encapsulation efficiency (EE), release profiles, stability, biocompatibility, protein adsorption, cytotoxicity, and anticancer effects were evaluated. Results: The nanoparticles exhibited high stability, size: 94.2 ± 0.9-144.0 ± 2.6 nm, PDI < 0.3, and zeta potential: -4.5 ± 0.7 to -16.3 ± 0.8 mV. Encapsulation of SV in all formulations enhanced cytotoxicity against A549 lung cancer cells, with NLC/LN/SV showing the highest activity and being chosen for further investigation. Sustained SV release over 72 h and EE > 95% was observed for NLC/LN/SV. SAXS/WAXS analysis revealed that LN altered the crystallographic structure of nanoparticles. NLC/LN/SV demonstrated excellent biocompatibility and developed a thin serum protein corona in vitro. Cellular studies showed efficient uptake by A549 cells, G0/G1 arrest, mitochondrial hyperpolarization, reactive oxygen species production, and enhanced cell death compared to free SV. NLC/LN/SV more effectively inhibited cancer cell migration than free SV. Conclusions: NLC/LN/SV represents a promising nanocarrier for SV repurposing, combining enhanced anticancer activity, biocompatibility, and sustained stability for potential lung cancer therapy.

Ferroptosis is a novel mode of iron-dependent non-apoptotic cell death that occurs mainly due to excessive accumulation of lipid peroxides. Numerous studies in recent years have shown that ferroptosis plays a vital role in the organism and has important interactions with immune cells. Ferroptosis has been shown to have great potential in tumour therapy through studying its mechanism of action. In addition, ferroptosis plays a major role in many types of tumour cells that can potently suppress the tumourigenesis and metastasis, provide a basis for the treatment of many malignant tumour diseases and become a novel therapeutic modality of antitumour immunity in the clinic. Current tumour immunotherapy for ferroptosis in combination with other conventional oncological modalities is not well elaborated. In this paper, we mainly discuss the connection of ferroptosis with immune cells and their mediated tumour immunotherapy in order to provide a better theoretical basis and new thinking about ferroptosis mediated antitumour immunity.

Triple-negative breast cancer (TNBC) is the most aggressive and malignant type of breast cancer with limited treatment options and poor prognosis. One of the most significant impediments in TNBC treatment is the high heterogeneity of this disease, as highlighted by the detection of several molecular subtypes of TNBC. Each subtype is driven by distinct mutations and pathway aberrations, giving rise to specific molecular characteristics closely connected to clinical behavior, outcomes, and drug sensitivity. This review summarizes the knowledge regarding TNBC molecular subtypes and how it can be harnessed to devise tailored treatment strategies instead of blindly using targeted drugs. We provide an overview of novel targeted agents and key insights about new treatment modalities with an emphasis on the androgen receptor signaling pathway, cancer stem cell-associated pathways, phosphatidylinositol 3-kinase (PI3K)/AKT pathway, growth factor signaling, and immunotherapy.

Metronomic chemotherapy (MC), long-term continuous administration of anticancer drugs, is gaining attention as an alternative to the traditional maximum tolerated dose (MTD) chemotherapy. By combining MC with other treatments, the therapeutic efficacy is enhanced while minimizing toxicity. MC employs multiple mechanisms, making it a versatile approach against various cancers. However, drug resistance limits the long-term effectiveness of MC, necessitating ongoing development of anticancer drugs. Traditional drug discovery is lengthy and costly due to processes like target protein identification, virtual screening, lead optimization, and safety and efficacy evaluations. Drug repurposing (DR), which screens FDA-approved drugs for new uses, is emerging as a cost-effective alternative. Both experimental and computational methods, such as protein binding assays, in vitro cytotoxicity tests, structure-based screening, and several types of association analyses (Similarity-Based, Network-Based, and Target Gene), along with retrospective clinical analyses, are employed for virtual screening. This review covers the mechanisms of MC, its application in various cancers, DR strategies, examples of repurposed drugs, and the associated challenges and future directions.

To enhance the efficacy of radiotherapy (RT) in human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC), we explored targeting ferroptosis, a regulated cell death process. We developed a gene signature associated with ferroptosis using Cox proportional hazard modeling in HPV-negative HNSCC patients who underwent RT. This ferroptosis-related gene signature (FRGS) was a significant predictor of overall survival and recurrence-free survival in HPV-negative HNSCC patients who received RT. Subtype B of the FRGS, characterized by decreased expression of ferroptosis inducers [nuclear receptor coactivator 4 (NCOA4) and natural resistance-associated macrophage protein 2 homolog/divalent metal transporter 1 (NRAMP2/DMT1)] and increased expression of suppressors [phospholipid hydroperoxide glutathione peroxidase (GPX4) and ferritin heavy chain (FTH1)], was associated with poorer prognosis, potentially indicating the inhibition of ferroptosis. Furthermore, our in vitro and in vivo studies demonstrated that treatment with statins, such as atorvastatin and simvastatin, induced ferroptosis and sensitized radioresistant HNSCC cells to irradiation, improving radiosensitivity and potentially enhancing the response to RT. Additionally, in xenograft models, the combination of statins and RT led to a significant reduction in tumor initiation. These findings provide valuable insights for enhancing treatment and improving prognosis in HPV-negative HNSCC by targeting ferroptosis and utilizing statins to sensitize tumors to RT-induced cell death.

The aim of the present study was to investigate the effects of targeting the mevalonate pathway (MVP) in rhabdomyosarcoma (RMS), a soft tissue tumor with a prevalence in young people.

In silico analyses of RNA datasets were performed to correlate MVP with RMS patient survival. The sensitivity of RMS cell lines to MVP inhibitors was assessed in vitro by analysis of cell growth (crystal violet and clonogenic assays), cell migration (wound healing assay), cell survival (neutral red assay), and oxidative stress (ROS assay). The effects of MVP inhibitors were tested in vivo by analyzing RMS xenografts grown in NOD/SCID mice. Quantification of protein targets was performed using immunoblotting or immunohistochemistry analyses.

In silico analysis showed upregulation of sterol regulatory element-binding protein 2 (SREBP2) and MVP genes, including 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR), farnesyl-diphosphate synthase (FDPS), squalene epoxidase (SQLE), which correlated with worse overall patient survival. Targeting of MVP in human RD and RH30 lines by inhibitors of SREBP2 (fatostatin), HMGCR (lovastatin and simvastatin), and FDPS (zoledronic acid) resulted in impaired cell growth, migration, and viability, and increased oxidative cell death in combination with actinomycin D. Conversely, cholesterol (CHO) supplementation enhanced cell growth and migration. Fatostatin and lovastatin produced rapid attenuation of Erk1/2 and Akt1 signaling in RMS lines, and oral administration of lovastatin reduced tumor mass growth of xenografted RD cells in NOD/SCID mice. Finally, we found that forced Akt1 activation in RD cells was sufficient to drive SREBP2, HMGCR and SQLE protein expression, promoting increased susceptibility to MVP inhibitors.

These data suggest that the Akt1, SREBP2 and MVP axis is critical for RMS tumor growth, migration, and oxidative stress protection primarily through maintaining adequate CHO levels that enable proper intracellular signaling. Therefore, stimulating CHO depletion via SREBP2 and MVP inhibition may represent a viable option to improve the combination therapy protocol, especially in pAkt1-positive RMS.

Carbohydrate kinases (CKs) are pivotal in various biological processes, including energy consumption, cell signaling, and biosynthesis. They are a group of enzymes that facilitate the phosphorylation of carbohydrates, playing a crucial role in cellular metabolism. These enzymes facilitate the transfer of a phosphate group from a high-energy donor like ATP to a specified location on a carbohydrate substrate. Dysregulated kinase activity drives tumor growth and progression. Inhibitors targeting these enzymes have been developed and used in cancer therapy. The CK family encompasses three major types: hexokinases, ribokinases, and phosphatidylinositol kinases, with inhibitors of paramount importance in cancer treatment. This review explores the role of CKs in cancer and its inhibitors, providing insights into improving existing inhibitors and designing new ones.

Gastric cancer (GC) is a prevalent malignant tumor of the digestive system that is often diagnosed at advanced stages owing to inconspicuous early symptoms and a lack of specific examination methods. Effective treatment of advanced stages remains challenging, emphasizing the need for new therapeutic targets. Metabolic reprogramming, a hallmark of tumors, plays a pivotal role in tumor progression, immune evasion, and immune surveillance. DNA damage-regulated autophagy modulator 1 (DRAM1) encodes a hexameric transmembrane protein that is predominantly located in lysosomes and induces autophagy; however, its mechanism of action in gastric cancer remains unclear. Our study found that elevated DRAM1 expression in patients with GC correlated with survival and prognosis. DRAM1 knockdown suppressed energy metabolism in GC cells through the PI3K/AKT/mTOR signaling pathway, thereby mitigating GC progression. Atorvastatin, a focus of recent tumor research, significantly enhanced apoptosis levels in DRAM1 knockdown GC cells compared to the control group. Therefore, through metabolic reprogramming, DRAM1 may serve as a potential therapeutic target for GC prevention.

Hepatocellular carcinoma (HCC) is a health problem due to multi-drug resistance (MDR). Codelivery of multiple oncotherapy in one cargo as chimeric cancer therapy (CCT) is suggested as a solution for MDR. This study aims to engineer chitosan-coated nanostructure lipid carriers (NLCs) loaded with gefitinib (GF) and simvastatin (SV) as CCT for HCC.

Both GF and SV-loaded nanostructure lipids carriers (GFSVNLC) and chitosan-capped GF and SV-loaded nanostructure lipids carriers (CGFSVNLC) formulations were assembled by top-down techniques. Moreover, particle size (PS), zeta potential (ZP), and polydispersity index (PDI) were measured by Zetasizer. The biosafety of GFSVNLC preparations was investigated by using erythrocytes as a biological model. The cytotoxic, and apoptotic effects of the prepared GFSVNLCs were investigated using HepG2 cell lines as a substitute model for HCC. The effect of GF, SV, and NLC composition on JNK3, HDAC6, and telomerase was studied using molecular docking simulation (MDS).

The present results revealed that the obtained GFSVNLC and CGFSVNLC have nanosized and consistent, CS coating shifts anionic ZP of GFSVNLC into CGFSVNLC with cationic ZP. Moreover, both formulations are biocompatible as indicated by their gentle effect on erythrocyte hemolysis. The treatment of HepG2 cells with GFSVNLC, and CGFSVNLC induced marked cell death compared to other groups with a decrease of IC50. Equally, the percentage of the apoptotic HepG2 cells was increased upon treatment of the cells with GFSV, GFSVNLC, and CGFSVNLC compared to the control group. Additionally, GF, SV, stearic acid (SA), and oleic acid (OA) modulate the activity of JNK3, HDAC6, and telomerase.

This study suggests CGFSVNLC achieves codelivery, selective targeting, and enhancing the synergistic effect of GF and SV for inducing HepG2 cell death. Mechanistically, CGFSVNLC inhibits key cascades implicated in MDR and HepG2 cell survival. CGFSVNLC is promising for overcoming drug resistance mechanisms and improving therapeutic outcomes against HepG2 cells.

Individuals with chronic inflammatory and immune disorders are at an increased risk of atherosclerotic events and premature cardiovascular (CV) disease. Despite extensive literature exploring the relationship between "non-traditional" atherosclerotic conditions and CV risk, many aspects remain unresolved, including the underlying mechanisms promoting the "non-traditional CV risk", the development of an innovative and comprehensive CV risk assessment tool, and recommendations for tailored interventions. This review aims to evaluate the available evidence on key "non-traditional" CV risk-enhancer conditions, with a focus on assessing and managing CV risk factors. We conducted a comprehensive review of 412 original articles, narrative and systematic reviews, and meta-analyses addressing the CV risk associated with "non-traditional" atherosclerotic conditions. The analysis examined the underlying mechanisms of these relationships and identified strategies for assessing and mitigating elevated risk. A major challenge highlighted is the difficulty in quantifying the contribution of individual risk factors and disease-specific elements to CV risk. While evidence supports the cardiovascular benefits of statins beyond lipid lowering, such as pleiotropic and endothelial effects, current guidelines lack specific recommendations for the use of statins or other therapies targeting non-traditional CV risk factors. Additionally, the absence of validated cardiovascular risk scores that incorporate non-traditional risk factors hinders accurate CV risk evaluation and management. The growing prevalence of "non-traditional CV risk-enhancer conditions" underscores the need for improved awareness of CV risk assessment and management. A thorough understanding of all contributing factors, including disease-specific elements, is crucial for accurate prediction of cardiovascular disease (CVD) risk. This represents an essential foundation for informed decision-making in primary and secondary prevention. We advocate for future research to focus on developing innovative, disease-specific CV risk assessment tools that incorporate non-traditional risk factors, recognizing this as a promising avenue for translational and clinical outcome research.