Preoperative prediction of MGMT promoter methylation in glioblastoma based on multiregional and multi-sequence MRI radiomics analysis.

O6-methylguanine-DNA methyltransferase (MGMT) has been demonstrated to be an important prognostic and predictive marker in glioblastoma (GBM). To establish a reliable radiomics model based on MRI data to predict the MGMT promoter methylation status of GBM. A total of 183 patients with glioblastoma were included in this retrospective study. The visually accessible Rembrandt images (VASARI) features were extracted for each patient, and a total of 14676 multi-region features were extracted from enhanced, necrotic, "non-enhanced, and edematous" areas on their multiparametric MRI. Twelve individual radiomics models were constructed based on the radiomics features from different subregions and different sequences. Four single-sequence models, three single-region models and the combined radiomics model combining all individual models were constructed. Finally, the predictive performance of adding clinical factors and VASARI characteristics was evaluated. The ComRad model combining all individual radiomics models exhibited the best performance in test set 1 and test set 2, with the area under the receiver operating characteristic curve (AUC) of 0.839 (0.709-0.963) and 0.739 (0.581-0.897), respectively. The results indicated that the radiomics model combining multi-region and multi-parametric MRI features has exhibited promising performance in predicting MGMT methylation status in GBM. The Modeling scheme that combining all individual radiomics models showed best performance among all constructed moels.

Lumican promotes calcific aortic valve disease through H3 histone lactylation.

BACKGROUND AND AIMS: Valve interstitial cells (VICs) undergo a transition to intermediate state cells before ultimately transforming into the osteogenic cell population, which is a pivotal cellular process in calcific aortic valve disease (CAVD). Herein, this study successfully delineated the stages of VIC osteogenic transformation and elucidated a novel key regulatory role of lumican (LUM) in this process. METHODS: Single-cell RNA-sequencing (scRNA-seq) from nine human aortic valves was used to characterize the pathological switch process and identify key regulatory factors. The in vitro, ex vivo, in vivo, and double knockout mice were constructed to further unravel the calcification-promoting effect of LUM. Moreover, the multi-omic approaches were employed to analyse the molecular mechanism of LUM in CAVD. RESULTS: ScRNA-seq successfully delineated the process of VIC pathological transformation and highlighted the significance of LUM as a novel molecule in this process. The pro-calcification role of LUM is confirmed on the in vitro, ex vivo, in vivo level, and ApoE-/-//LUM-/- double knockout mice. The LUM induces osteogenesis in VICs via activation of inflammatory pathways and augmentation of cellular glycolysis, resulting in the accumulation of lactate. Subsequent investigation has unveiled a novel LUM driving histone modification, lactylation, which plays a role in facilitating valve calcification. More importantly, this study has identified two specific sites of histone lactylation, namely, H3K14la and H3K9la, which have been found to facilitate the process of calcification. The confirmation of these modification sites' association with the expression of calcific genes Runx2 and BMP2 has been achieved through ChIP-PCR analysis. CONCLUSIONS: The study presents novel findings, being the first to establish the involvement of lumican in mediating H3 histone lactylation, thus facilitating the development of aortic valve calcification. Consequently, lumican would be a promising therapeutic target for intervention in the treatment of CAVD.

Anticancer efficacy triggered by synergistically modulating the homeostasis of anions and iron: Design, synthesis and biological evaluation of dual-functional squaramide-hydroxamic acid conjugates.

Targeting the homeostasis of anions and iron has emerged as a promising therapeutic approach for the treatment of cancers. However, single-targeted agents often fall short of achieving optimal treatment efficacy. Herein we designed and synthesized a series of novel dual-functional squaramide-hydroxamic acid conjugates that are capable of synergistically modulating the homeostasis of anions and iron. Among them, compound 16 exhibited the most potent antiproliferative activity against a panel of selected cancer cell lines, and strong in vivo anti-tumor efficacy. This compound effectively elevated lysosomal pH through anion transport, and reduced the levels of intracellular iron. Compound 16 could disturb autophagy in A549 cells and trigger robust apoptosis. This compound caused cell cycle arrest at the G1/S phase, altered the mitochondrial function and elevated ROS levels. The present findings clearly demonstrated that synergistic modulation of anion and iron homeostasis has high potentials in the development of promising chemotherapeutic agents with dual action against cancers.

Two new quinoline alkaloid with neuroprotective activities from Xylaria longipes.

Two new quinoline alkaloids with an α, ß-unsaturated amide side chain, xylarinines A and B (1 and 2), were isolated from the ethyl acetate extracts of Xylaria longipes solid fermentation. The structures of these were primarily determined though NMR and HRESIMS data analysis. The absolute configuration of compound 1 was assigned using experimental and calculated ECD data. The neuroprotective effects of compounds 1 and 2 against glutamate-induced damage in PC12 cells were evaluated in vitro bioassay. The results demonstrated that both compounds significantly improved cell viability, inhibited apoptosis, decreased malondialdehyde (MDA) levels, increased superoxide dismutase (SOD) and glutathione (GSH) levels, and reduced intracellular reactive oxygen species (ROS) accumulation. These findings suggested that these mechanisms contribute to the neuroprotective effects of the compounds.

A pair of new chromone enantiomers from Xylaria nigripes.

A pair of new chromone derivative enantiomers, (+)-xylarichromone A (1a) and (-)-xylarichromone A (1b), were isolated from the solid fermentation of Xylaria nigripes. The planar structure of 1 was determined by extensive NMR spectroscopic data, and its absolute configuration was assigned by comparison the ECD spectra with the known chromone derivatives. Compound 1 was the first chromone derivative reported from this medicinal fungus. The neuroprotective effects of 1 against oxygen and glucose deprivation (OGD) induced pheochromocytoma-12 cells (PC12) injury was investigated.

Design, Synthesis, and Antitumor Efficacy of Substituted 2-Amino[1,2,4]triazolopyrimidines and Related Heterocycles as Dual Inhibitors for Microtubule Polymerization and Janus Kinase 2.

Preclinical and clinical studies have demonstrated the synergistic effect of microtubule-targeting agents in combination with Janus kinase 2 (JAK2) inhibitors, prompting the development of single agents with enhanced therapeutic efficacy by dually inhibiting tubulin polymerization and JAK2. Herein, we designed and synthesized a series of substituted 2-amino[1,2,4]triazolopyrimidines and related heterocycles as dual inhibitors for tubulin polymerization and JAK2. Most of these compounds exhibited potent antiproliferative activity against the selected cancer cells, with compound 7g being the most active. This compound effectively inhibits both tubulin assembly and JAK2 activity. Furthermore, phosphorylated compound 7g (i.e., compound 7g-P) could efficiently convert to compound 7g in vivo. Compound 7g, whether it was administered directly or in the form of a phosphorylated prodrug (i.e., compound 7g-P), significantly inhibited the growth of A549 xenografts in nude mice. The present findings strongly suggest that compound 7g represents a promising chemotherapeutic agent with high antitumor efficacy.

Tumor Microenvironment Activated Photoacoustic-Fluorescence Bimodal Nanoprobe for Precise Chemo-immunotherapy and Immune Response Tracing of Glioblastoma.

Synergistic therapy strategy and prognostic monitoring of glioblastoma's immune response to treatment are crucial to optimize patient care and advance clinical outcomes. However, current systemic temozolomide (TMZ) chemotherapy and imaging methods for in vivo tracing of immune responses are inadequate. Herein, we report an all-in-one theranostic nanoprobe (PEG/αCD25-Cy7/TMZ) for precise chemotherapy and real-time immune response tracing of glioblastoma by photoacoustic-fluorescence imaging. The nanoprobe was loaded with TMZ and targeted regulatory T lymphocyte optical dye αCD25-Cy7 encapsulated by glutathione-responsive DSPE-SS-PEG2000. The results showed that the targeted efficiency of the nanoprobe to regulatory T lymphocytes is up to 92.3%. The activation of PEG/αCD25-Cy7/TMZ by glutathione enhanced the precise delivery of TMZ to the tumor microenvironment for local chemotherapy and monitored glioblastoma's boundary by photoacoustic-fluorescence imaging. Immunotherapy with indoleamine 2,3-dioxygenase inhibitors after chemotherapy could promote immunological responses and reduce regulatory T lymphocyte infiltration, which could improve the survival rate. Photoacoustic imaging has in real-time and noninvasively depicted the dynamic process of immune response on a micrometer scale, showing that the infiltration of regulatory T lymphocytes after chemotherapy was up-regulated and would down-regulate after IDO inhibitor treatment. This all-in-one theranostic strategy is a promising method for precisely delivering TMZ and long-term dynamically tracing regulatory T lymphocytes to evaluate the immune response in situ for accurate tumor chemo-immunotherapy.

Integrated urban water management by coupling iron salt production and application with biogas upgrading.

Integrated urban water management is a well-accepted concept for managing urban water. It requires efficient and integrated technological solutions that enable system-wide gains via a whole-of-system approach. Here, we create a solid link between the manufacturing of an iron salt, its application in an urban water system, and high-quality bioenergy recovery from wastewater. An iron-oxidising electrochemical cell is used to remove CO2 (also H2S and NH3) from biogas, thus achieving biogas upgrading, and simultaneously producing FeCO3. The subsequent dose of the electrochemically produced FeCO3 to wastewater and sludge removes sulfide and phosphate, and enhances sludge settleability and dewaterability, with comparable or superior performance compared to the imported and hazardous iron salts it substitutes (FeCl2, and FeCl3). The process enables water utilities to establish a self-reliant and more secure supply chain to meet its demand for iron salts, at lower economic and environmental costs, and simultaneously achieve recovery of high-quality bioenergy.

Royal jelly acid suppresses hepatocellular carcinoma tumorigenicity by inhibiting H3 histone lactylation at H3K9la and H3K14la sites.

BACKGROUND AND PURPOSE: Human hepatocellular carcinoma (HCC) features include enhanced glycolysis and elevated lactate concentrations. Accumulation of lactate during metabolism provides a precursor for histone lysine modification. This study was designed to determine whether royal jelly acid (RJA) acts against HCC through the lactate modification pathway. EXPERIMENTAL APPROACH: The effects of RJA on Hep3B and HCCLM3 cell invasion, migration, proliferation, and apoptosis were investigated using cell scratching, colony formation assay, flow cytometry, western blotting, and real-time qPCR, gas chromatography, and RNA sequencing to determine the pathways and molecular targets involved. Tumor xenografts were used to evaluate the anti-HCC effects of RJA in vivo. In-cell Western blotting and expression correlation analysis were applied to confirm the associations between H3 histone lactylation and the antitumor effects of RJA. KEY RESULTS: RJA has good antitumor effects in vivo and in vitro. Multi-omics analysis with metabolome and transcriptome determined that the glycolytic metabolic pathway provided the principle antitumor effect of RJA. Further mechanistic studies showed that RJA inhibited HCC development by interfering with lactate production and inhibiting H3 histone lactylation at H3K9la and H3K14la sites. CONCLUSIONS AND IMPLICATIONS: This study first demonstrated that RJA exerts antitumor effects by affecting the glycolytic pathway. RJA could regulate the lactylation of H3K9la and H3K14la sites on H3 histone using lactate as a clue in the glycolytic pathway. Therefore, the lactylation of H3 histone is vital in exerting the antitumor effect of RJA, providing new evidence for screening and exploring antitumor drug mechanisms in the later stage.

Multi-Biomarkers Panel in Identifying Benign and Malignant Lung Diseases and Pathological Types of Lung Cancer.

With the discovery of many tumor markers, there are new strategies for the early diagnosis and treatment of lung cancer and the prediction of prognosis. We examined the multi-protein markers panel (4MP, consisting of Pro-SFTPB, CA125, Cyfra21-1, and CEA) diagnosis performance in differentiating benign and malignant lung diseases and identifying pathological types of lung cancer. Meantime, the complementary performance of three conventional tumor markers (NSE, SCC, and Pro-GRP) for 4MP was assessed. A total of 294 patients with lung cancer or benign lung disease are contained in this study. The AUCs of 4MP and 7MP (NSE, SCC, Pro-GRP, and 4MP) in distinguishing benign lung disease and lung cancer were 0.808 and 0.832, respectively. In distinguishing SQCLC and SCLC, the AUCs were 0.716 and 0.985, respectively. In distinguishing LADC and SCLC, the AUCs were 0.849 and 0.998, respectively. This study demonstrated that 4MP can distinguish lung cancer from benign disease. Traditional biomarkers NSE, SCC, and Pro-GRP can significantly improve the performance of 4MP in the differentiation of LADC, SQCLC, and SCLC, which is expected to contribute to the accurate diagnosis and personalized treatment of patients.

Effectiveness and safety of tenofovir amibufenamide and its comparison with tenofovir alafenamide in patients with chronic hepatitis B: results from a retrospective real-world study.

Background/aim: Tenofovir amibufenamide (TMF) has shown potent antiviral efficacy in randomized clinical studies. This study aimed to reveal the effectiveness and safety of tenofovir amibufenamide in the real world and compared tenofovir amibufenamide to tenofovir alafenamide (TAF) in patients with chronic hepatitis B (CHB). Methods: In this retrospective study, tenofovir amibufenamide-treated chronic hepatitis B patients were divided into treatment-naive (TN) and treatment-experienced (TE) groups. Furthermore, tenofovir alafenamide-treated patients were enrolled using the propensity score matching method (PSM). We assessed the virological response (VR, HBV DNA < 100 IU/mL) rate, renal function, and blood lipid changes during 24 weeks of treatment. Results: Virologic response rates at week 24 were 93% (50/54) in the treatment-naive group and 95% (61/64) in the treatment-experienced group. The ratios of alanine transaminase (ALT) normalization were 89% (25/28) in the treatment-naive group and 71% (10/14) in the treatment-experienced group (p = 0.306). Additionally, serum creatinine decreased in both the treatment-naive and treatment-experienced groups, (-4.44 ± 13.55 µmol/L vs. -4.14 ± 9.33 µmol/L, p = 0.886), estimated glomerular filtration rate (eGFR) increased (7.01 ± 12.49 ml/min/1.73 m2 vs. 5.50 ± 8.16 ml/min/1.73 m2, p = 0.430), and low-density lipoprotein cholesterol (LDL-C) levels increased (0.09 ± 0.71 mmol/L vs. 0.27 ± 0.68 mmol/L, p = 0.152), whereas total cholesterol/high-density lipoprotein cholesterol (TC/HDL-C) levels decreased continuously from 3.26 ± 1.05 to 2.49 ± 0.72 in the treatment-naive group and from 3.31 ± 0.99 to 2.88 ± 0.77 in the treatment-experienced group. Using propensity score matching, we further compared virologic response rates between the tenofovir amibufenamide and tenofovir alafenamide cohorts. Virologic response rates in treatment-naive patients were higher in the tenofovir amibufenamide cohort [92% (35/38) vs. 74% (28/38), p = 0.033]. Virologic response rates in treatment-experienced patients showed no statistical difference between the tenofovir amibufenamide and tenofovir alafenamide cohorts. Conclusion: Tenofovir amibufenamide had profound antiviral effectiveness and no adverse effects on renal function or blood lipids. Additionally, tenofovir amibufenamide was more efficient than tenofovir alafenamide in inhibiting viral replication, which needs to be demonstrated in future studies.

Multi-clinical index classifier combined with AI algorithm model to predict the prognosis of gallbladder cancer.

Objectives: It is significant to develop effective prognostic strategies and techniques for improving the survival rate of gallbladder carcinoma (GBC). We aim to develop the prediction model from multi-clinical indicators combined artificial intelligence (AI) algorithm for the prognosis of GBC. Methods: A total of 122 patients with GBC from January 2015 to December 2019 were collected in this study. Based on the analysis of correlation, relative risk, receiver operator characteristic curve, and importance by AI algorithm analysis between clinical factors and recurrence and survival, the two multi-index classifiers (MIC1 and MIC2) were obtained. The two classifiers combined eight AI algorithms to model the recurrence and survival. The two models with the highest area under the curve (AUC) were selected to test the performance of prognosis prediction in the testing dataset. Results: The MIC1 has ten indicators, and the MIC2 has nine indicators. The combination of the MIC1 classifier and the "avNNet" model can predict recurrence with an AUC of 0.944. The MIC2 classifier and "glmet" model combination can predict survival with an AUC of 0.882. The Kaplan-Meier analysis shows that MIC1 and MIC2 indicators can effectively predict the median survival of DFS and OS, and there is no statistically significant difference in the prediction results of the indicators (MIC1: χ2 = 6.849, P = 0.653; MIC2: χ2 = 9.14, P = 0.519). Conclusions: The MIC1 and MIC2 combined with avNNet and mda models have high sensitivity and specificity in predicting the prognosis of GBC.

Two New Compounds from the Fungus Xylaria nigripes.

In the process of discovering more neural-system-related bioactive compounds from Xylaria nigripes, xylariamino acid A (1), a new amino acid derivative, and a new isovaleric acid phenethyl ester (2) were isolated and identified. Their structures and absolute configurations were determined by analyses of IR, HRESIMS, NMR spectroscopic data, and gauge-independent atomic orbital (GIAO) NMR calculation, as well as electronic circular dichroism (ECD) calculation. The isolated compounds were evaluated for their neuroprotective effects against damage to PC12 cells by oxygen and glucose deprivation (OGD). Compounds 1 and 2 can increase the viability of OGD-induced PC12 cells at all tested concentrations. Moreover, compound 2 (1 µmol L-1) can significantly reduce the percentage of apoptotic cells.

Atractylenolide-1 affects glycolysis/gluconeogenesis by downregulating the expression of TPI1 and GPI to inhibit the proliferation and invasion of human triple-negative breast cancer cells.

Atractylenolide-1 (AT-1) is a major octanol alkaloid isolated from Atractylodes Rhizoma and is widely used to treat various diseases. However, few reports have addressed the anticancer potential of AT-1, and the underlying molecular mechanisms of its anticancer effects are unclear. This study aimed to assess the effect of AT-1 on triple-negative breast cancer (TNBC) cell proliferation and migration and explore its potential molecular mechanisms. Cell invasion assays confirmed that the number of migrating cells decreased after AT-1 treatment. Colony formation assays showed that AT-1 treatment impaired the ability of MDA-MB-231 cells to form colonies. AT-1 inhibited the expression of p-p38, p-ERK, and p-AKT in MDA-MB-231 cells, significantly downregulated the proliferation of anti-apoptosis-related proteins CDK1, CCND1, and Bcl2, and up-regulated pro-apoptotic proteins Bak, caspase 3, and caspase 9. The gas chromatography-mass spectroscopy results showed that AT-1 downregulated the metabolism-related genes TPI1 and GPI through the glycolysis/gluconeogenesis pathway and inhibited tumor growth in vivo. AT-1 affected glycolysis/gluconeogenesis by downregulating the expression of TPI1 and GPI, inhibiting the proliferation, migration, and invasion of (TNBC) MDA-MB-231 cells and suppressing tumor growth in vivo.

Antiviral Therapy Favors a Lower Risk of Liver Cirrhosis in HBeAg-negative Chronic Hepatitis B with Normal Alanine Transaminase and HBV DNA Positivity.

Background and Aims: Direct evidence on the outcomes of hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) patients with normal alanine transaminase after long-term antiviral treatment is lacking. Methods: HBeAg-negative patients with normal ALT and positive HBV DNA (≥20 IU/mL) were retrospectively enrolled. The endpoints included virological response (HBV DNA<100 IU/mL), changes in aspartate aminotransferase to platelet ratio index (APRI) and fibrosis-4 index (FIB-4), and the incidence of liver nodules, cirrhosis, and hepatocellular carcinoma (HCC). Results: This cohort (n=194) was divided into three subgroups, untreated (n=67), treatment-continued (n=87), and treatment-discontinued patients (n=40), with a median follow-up of 54 months. The treatment-continued group achieved 100% (95% CI: 94.7-100) virological response, and significantly reduced APRI and FIB-4 scores (both p<0.001). The risk of liver nodules and cirrhosis in that group was reduced by 76% (HR: 0.24, 95% CI: 0.11-0.54, p<0.001) and 89% (HR: 0.11, 95% CI: 0.14-0.91, p=0.041) vs. the untreated group and by 77% (HR: 0.23, 95% CI: 0.10-0.49, p<0.001) and 95% (HR: 0.05, 95% CI: 0.01-0.44, p=0.006) vs. the treatment-discontinued group. For patients with HBV DNA≥2,000 IU/mL, adherence to treatment lowered the risks of liver cirrhosis by 92% (95% CI: 0.01-0.67) and 93% (95% CI: 0.01-0.53) vs. the untreated and treatment-discontinued patients, respectively. No patient adhering to treatment developed HCC, but one in each of the remaining groups did. Conclusions: Continuous nucleos(t)ide analog (NA) treatment has a satisfactory effectiveness and helps to lower the risk of liver cirrhosis in HBeAg-negative CHB patients with normal alanine transaminase, especially in those with HBV DNA≥2,000 IU/mL.

Expanding antiviral therapy indications for HBeAg-negative chronic hepatitis B patients with normal ALT and positive HBV DNA.

With the improved efficacy and accessibility of antiviral agents as well as the concerns about disease progression, there is a hot discussion on whether HBeAg-negative chronic hepatitis B (CHB) patients with normal alanine aminotransferase (ALT) and positive HBV DNA should be treated. According to the international guidelines on the stages of the natural history of HBV infection, HBeAg-negative CHB patients with normal ALT and positive HBV DNA can be divided into two groups: one is the well-known "inactive carrier phase", which is defined as serum HBV DNA < 2000 IU/ml and no significant liver inflammation; and the other is the "indeterminate phase", which is defined as serum HBV DNA ≥ 2000 IU/mL regardless of the pathological changes in liver tissue, or HBV DNA < 2000 IU/mL but accompanied by significant pathological changes in the liver. In this minireview, we will expound the disease characteristics, disease progression, and clinical management status of these two groups. Based on the analysis, we propose that HBeAg-negative patients with normal ALT but detectable serum HBV DNA should be treated, regardless of their age, family history of hepatocellular carcinoma (HCC) or the severity of liver necroinflammation. Expanding the indications of antiviral therapy will help improve the survival and quality of life of patients by preventing disease progression, and consequently reduce the risk of HCC development.

The role of the gut microbiota and probiotics associated with microbial metabolisms in cancer prevention and therapy.

Cancer is the second leading cause of elevated mortality worldwide. Thus, the development of drugs and treatments is needed to enhance the survival rate of the cancer-affected population. Recently, gut microbiota research in the healthy development of the human body has garnered widespread attention. Many reports indicate that changes in the gut microbiota are strongly associated with chronic inflammation-related diseases, including colitis, liver disease, and cancer within the intestine and the extraintestinal tract. Different gut bacteria are vital in the occurrence and development of tumors within the gut and extraintestinal tract. The human gut microbiome has significant implications for human physiology, including metabolism, nutrient absorption, and immune function. Moreover, diet and lifestyle habits are involved in the evolution of the human microbiome throughout the lifetime of the host and are involved in drug metabolism. Probiotics are a functional food with a protective role in cancer development in animal models. Probiotics alter the gut microbiota in the host; thus, beneficial bacterial activity is stimulated, and detrimental activity is inhibited. Clinical applications have revealed that some probiotic strains could reduce the occurrence of postoperative inflammation among cancer patients. An association network was constructed by analyzing the previous literature to explore the role of probiotics from the anti-tumor perspective. Therefore, it provides direction and insights for research on tumor treatment.

Tumor-Homing and Immune-Reprogramming Cellular Nanovesicles for Photoacoustic Imaging-Guided Phototriggered Precise Chemoimmunotherapy.

Many studies have focused on developing effective therapeutic strategies to selectively destroy primary tumors, eliminate metastatic lesions, and prevent tumor recurrence with minimal side effects on normal tissues. In this work, we synthesized engineered cellular nanovesicles (ECNVs) with tumor-homing and immune-reprogramming functions for photoacoustic (PA) imaging-guided precision chemoimmunotherapy. M1-macrophage-derived cellular nanovesicles (CNVs) were loaded with gold nanorods (GNRs), gemcitabine (GEM), CpG ODN, and PD-L1 aptamer. The good histocompatibility and tumor-homing effect of CNVs improved drug retention in the bloodstream and led to their enrichment in tumor tissues. Furthermore, the photothermal ability of GNRs enabled PA imaging-guided drug release. GEM induced tumor immunogenic cell death (ICD), and CpG ODN promoted an immune response to the antigens released by ICD, leading to long-term specific antitumor immunity. In addition, the PD-L1 aptamer relieved the inhibitory effect of the PD1/PD-L1 checkpoint on CD8+ T-cells and augmented the immunotherapeutic effect. The synergistic innate and adaptive immune responses enhanced the antitumor effect of ECNVs. In summary, this nanoplatform integrates local targeted photothermal therapy with extensive progressive chemotherapy and uses ICD to reshape the immune microenvironment for tumor ablation.

Perspectives and mechanisms for targeting ferroptosis in the treatment of hepatocellular carcinoma.

Ferroptosis is a novel process of regulated cell death discovered in recent years, mainly caused by intracellular lipid peroxidation. It is morphologically manifested as shrinking of mitochondria, swelling of cytoplasm and organelles, rupture of plasma membrane, and formation of double-membrane vesicles. Work done in the past 5 years indicates that induction of ferroptosis is a promising strategy in the treatment of hepatocellular carcinoma (HCC). System xc - /GSH/GPX4, iron metabolism, p53 and lipid peroxidation pathways are the main focus areas in ferroptosis research. In this paper, we analyze the ferroptosis-inducing drugs and experimental agents that have been used in the last 5 years in the treatment of HCC. We summarize four different key molecular mechanisms that induce ferroptosis, i.e., system xc - /GSH/GPX4, iron metabolism, p53 and lipid peroxidation. Finally, we outline the prognostic analysis associated with ferroptosis in HCC. The findings summarized suggest that ferroptosis induction can serve as a promising new therapeutic approach for HCC and can provide a basis for clinical diagnosis and prevention of this disease.