Cancer remains a significant barrier to human longevity and a leading cause of mortality worldwide. Despite advancements in cancer therapies, challenges such as cellular toxicity and drug resistance to chemotherapy persist. Regulated cell death (RCD), once regarded as a passive process, is now recognized as a programmed mechanism with distinct biochemical and morphological characteristics, thereby presenting new therapeutic opportunities. Ferroptosis, a novel form of RCD characterized by iron-dependent lipid peroxidation and unique mitochondrial damage, differs from apoptosis, autophagy, and necroptosis. It is driven by reactive oxygen species (ROS)-induced lipid peroxidation and is implicated in tumorigenesis, anti-tumor immunity, and resistance, particularly in tumors undergoing epithelial-mesenchymal transition. Moreover, ferroptosis is associated with ischemic organ damage, degenerative diseases, and aging, regulated by various cellular metabolic processes, including redox balance, iron metabolism, and amino acid, lipid, and glucose metabolism. This review focuses on the role of epigenetic factors in tumor ferroptosis, exploring their mechanisms and potential applications in cancer therapy. It synthesizes current knowledge to provide a comprehensive understanding of epigenetic regulation in tumor cell ferroptosis, offering insights for future research and clinical applications.

Breast cancer is the most prevalent form of malignant tumor that frequently metastasizes to axillary lymph nodes (LNs). Nonetheless, the precise mechanisms underlying alterations in the tumor microenvironment (TME) in LN metastasis in breast cancer remain poorly understood. Single-cell RNA sequencing of 28 LN samples from 23 patients is performed, and a comprehensive landscape of the entire ecosystem is generated. Ten major cell types are identified, with the subclusters of each major cell type exhibiting diverse characteristics. Furthermore, multiple signatures are collected to evaluate the key components of the subclusters using multi-omics methodologies. This study finds that myCAFs may hasten LN metastasis, and observed a notable increase in APOE+ macrophages and a higher proportion of exhausted CD8+ T cells, contributing to the immunosuppressive TME. Moreover, cancer cells in metastatic lesions exhibited diverse expression patterns linked to proliferation, metastasis, oxidative phosphorylation, hypoxia, and interferon responses. Using multi-omics approaches and experimental validations, it determines that GLO1 can promote lymphatic angiogenesis, metastasis, and inhibit the proteasomal degradation of GSS, thereby maintaining intracellular glutathione (GSH) and reactive oxygen species (ROS) balance. Collectively, the study offers novel perspectives on the microenvironment remodeling of breast cancer LN metastases, suggesting that GLO1 may be a promising therapeutic target.

Liver fibrosis is characterized by an excessive accumulation of extracellular matrix (ECM) and the activation of hepatic stellate cells (HSCs), which are influenced by epitranscriptomic and epigenetic factors. Recent advancements in epigenetic and epitranscriptomic research have revealed new opportunities for therapeutic interventions, particularly through the regulation of ferroptosis, a type of programmed cell death that is specifically linked to iron-dependent lipid peroxidation. In the context of liver fibrosis, a progressive scarring process that can progress to cirrhosis and ultimately end-stage liver disease, targeting these regulatory mechanisms to modulate ferroptosis presents a promising therapeutic strategy. This review aims to consolidate current knowledge on the epigenetic and epitranscriptomic control of ferroptosis and investigate its potential implications for the treatment of liver fibrosis.

Lung cancer (LC) is the leading cause of cancer-related deaths and the second most commonly diagnosed malignancy worldwide. Lung adenocarcinoma (LUAD) and lung squamous cell LC (LUSCC) are the most common subtypes of non-small cell LC (NSCLC). Early diagnosis of LC can be challenging due to a lack of biomarkers. The overall survival (OS) of patients with NSCLC is still poor despite the enormous efforts that have been made to develop novel treatments. Understanding fundamental molecular and genetic mechanisms is necessary to develop new therapeutic approaches for NSCLC. A recently identified type of programmed cell death known as ferroptosis is one potential approach. Ferroptosis causes oxidative damage and the death of cancerous cells by peroxidizing unsaturated phospholipids and accumulating reactive oxygen species (ROS) in an iron-dependent manner. Ferroptosis-related gene (FRG) signatures have recently been evaluated for their ability to predict patient OS and prognosis. These analyses show FRGs are involved in cancer progression, and may serve as promising biomarkers for tumor diagnosis and therapy. Moreover, we summarize the current pharmaceutical options of ferroptosis induction and their underlying molecular mechanism in LC. Therefore, this review aims to provide a comprehensive summary of FRG-based prognostic models, their associated metabolic and signaling pathways, and promising therapeutic options for ferroptosis induction in NSCLC.

Methylation-related regulators may be involved in the prognostic prediction of esophageal squamous cell carcinoma (ESCC). Our study aimed to apply bioinformatics to screen methylation-related regulators for the construction of a prognostic model for patients with ESCC and to assess their diagnostic value and correlation with immune infiltration.

Prognosis-related genes were identified from The Cancer Genome Atlas (TCGA) database. Methylation-associated genes were filtered using the GeneCards database. We used the least absolute shrinkage and selection operator (LASSO) and Cox proportional hazards regression to identify the prognostic indicators. We applied the single-sample gene set enrichment analysis (ssGSEA) to clarify the relationship between prognostic indicators and immune infiltration in patients with ESCC (n=82).

We constructed a prognostic model using methylation-related regulators homocysteine-inducible ER protein with ubiquitin-like domain 1 (HERPUD1), trans-2,3-enoyl-CoA reductase (TECR), melanoma antigen gene A11 (MAGEA11), and NOP2/Sun RNA methyltransferase 6 (NSUN6) to evaluate the prognosis of patients with ESCC. A higher prognostic risk score was associated with shorter overall survival (OS) in patients with ESCC [hazard ratio (HR) =5.77, 95% confidence interval (CI): 2.13-15.58; P<0.001]. Time-dependent area under the curve (AUC) analysis revealed that HERPUD1, TECR, MAGEA11, and NSUN6 had high prognostic predictive value at different time points. Furthermore, we found that the combined diagnostic model based on HERPUD1, TECR, MAGEA11, and NSUN6 had excellent diagnostic efficacy for ESCC (AUC =0.911; 95% CI: 0.888-0.935). Finally, the ssGSEA algorithm showed that HERPUD1 was significantly positively correlated with immune infiltration at both the cellular and genetic levels, while TECR showed a significant negative correlation with immune infiltration levels.

Our prognostic model, built with the methylation-related regulators HERPUD1, TECR, MAGEA11, and NSUN6, could effectively predict prognosis in patients with ESCC, enhance diagnostic efficacy, and reflect immune cell infiltration in their microenvironment. Our findings are hypothesis generating and larger confirmatory studies are needed to validate our results.

Ferroptosis is a novel type of programmed cell death caused by excessive iron-dependent lipid peroxidation. According to various studies, there may be a link between ferroptosis and lipid metabolism. However, few studies have been reported on the lipid metabolism of ferroptosis in acute myeloid leukemia (AML). Here, we analyzed the relationship between lipid metabolism and ferroptosis in AML cells to explore new clinical treatment strategies. This study found that 12 fatty acids were significantly changed in acute myeloid leukemia cell ferroptosis, including dihomo-γ-linolenic acid (DGLA), arachidonic acid (AA), docosahexaenoic acid (DHA), etc. Exogenous DGLA substantially increases the sensitivity to ferroptosis and induces ferroptosis alone in AML cells. In addition, acyl-CoA synthetase long-chain family member 4 (ACSL4) knockout significantly inhibited DGLA-induced AML cells ferroptosis, and ACSL4 regulates DGLA-associated lipid synthesis to affect the sensitivity of AML cells to ferroptosis. Collectively, our studies indicate that a DGLA-enriched diet significantly restricted the growth of leukemia cells as well as induced ferroptosis in vivo.

We aimed to elucidate the roles of ferroptosis-associated differentially expressed genes (DEGs) in glioblastoma and provide a comprehensive resource for researchers in the field of glioblastoma cell ferroptosis.

We used RNA sequencing to identify the DEGs associated with erastin-induced ferroptosis in glioblastoma cells. We further unraveled the biological functions and clinical implications of cold-inducible RNA-binding protein (CIRBP) in the context of glioblastoma by using a multifaceted approach, encompassing gene expression profiling, survival analysis, and functional assays to elucidate its role in glioblastoma cell mortality and its potential influence on patient prognosis.

We identified and validated the gene encoding CIRBP, the expression of which is altered during glioblastoma ferroptosis. Our findings highlight the relationship between CIRBP expression and ferroptosis in glioblastoma cells. We demonstrated that CIRBP modulates key aspects of cell death, thereby altering the sensitivity of glioblastoma cells to erastin-induced ferroptosis. A prognostic model, constructed based on CIRBP expression levels, revealed an association between lower CIRBP levels and poorer prognosis in glioma patients; this finding was corroborated by our comprehensive in vitro and in vivo assays that highlighted the impact of modulating CIRBP expression on glioblastoma cell viability and ferroptotic response.

Our research unravels the complex molecular dynamics of ferroptosis in glioblastoma and underscores CIRBP as a potential biomarker and therapeutic target. This improved understanding of the role of CIRBP in ferroptosis paves the way for more precise and efficacious treatments for glioblastoma, potentially improving patient outcomes.

Gastric cancer (GC) remains a significant global health challenge, particularly prevalent in East Asia. Despite advancements in various treatment modalities, the prognosis for patients, especially those in advanced stages, remains poor, highlighting the need for innovative therapeutic approaches. This review explores the promising potential of diterpenes, naturally occurring compounds with robust anticancer properties, derived from diverse sources such as plants, marine organisms, and fungi. Diterpenes have shown the ability to influence reactive oxygen species (ROS) generation, ferroptosis, and autophagy, positioning them as attractive candidates for novel cancer therapies. This review explores the mechanisms of action of diterpenes and their clinical implications for the treatment of GC. Additionally, it addresses the challenges in translating these compounds from preclinical studies to clinical applications, emphasizing the need for further research to enhance their therapeutic profiles and minimize potential side effects. The discussion underscores the importance of diterpenes in future anticancer strategies, particularly in the fight against gastric cancer.

Corosolic acid (CA), a naturally occurring pentacyclic triterpenoid is renowned for its anticancer attributes. Previous studies have predominantly centered on the anticancer properties of CA in lung cancer, specifically its role in inducing apoptosis, however, investigations regarding its involvement in ferroptosis have been scarce.

The apoptotic and proliferative effects were evaluated by CCK8 and colony formation assay. Cell death and ROS generation were measured to assess the response of CA to iron death induction. Scratch and invasion assays were performed to verify the effect of CA on the invasive ability of lung cancer cells. Protein and mRNA expression were analyzed using Western blotting and qPCR. The CHX assay was carried out to detect protein half-life. Metabolite levels were measured with appropriate kits. Protein expression was detected through IF and IHC. A xenograft tumor model was established to investigate the inhibitory effect of CA on lung cancer in vivo.

The current findings revealed that CA exerts its anticancer effect by inducing cell death, accompanied by the accumulation of lipid reactive oxygen species (ROS), hinting at the possible involvement of ferroptosis. Our experimental results further substantiated the significance of ferroptosis in the CA anticancer mechanism, as ferroptosis inhibitors were found to effectively rescue CA-induced cell death. Significantly, we demonstrated for the first time that CA could induce ferroptosis further by suppressing EMT in lung cancer cells. Additionally, CA could regulate GPX4 to induce ferroptosis, interestingly, CA downregulated GSH synthetase by inhibiting YAP rather than GPX4, thereby reducing GSH, inducing ferroptosis, and further suppressing EMT in lung cancer cells.We also discovered that GSS is a crucial downstream target of YAP in regulating GSH. Moreover, a xenograft mouse model indicated that CA could trigger ferroptosis in lung cancer cells by regulating YAP expression and GSH levels.

CA inhibited lung cancer cell metastasis by inducing ferroptosis. Our data offer the first evidence that CA induces ferroptosis in lung cancer cells by regulating YAP/GSS to modulate GSH, thereby further suppressing EMT. These results imply the potential of CA as an inducer of ferroptosis to inhibit lung cancer metastasis.

Ferroptosis is a newly discovered form of cell death that is influenced by iron levels and is triggered by cellular metabolism and excessive lipid peroxidation. Epigenetic regulation plays a crucial role in the development and progression of diseases, making it essential to understand these mechanisms in order to identify potential targets for drug development and clinical treatment. The intersection of ferroptosis and epigenetics has opened up new avenues for research in drug development, offering innovative strategies for combating diseases. Recent studies have shown that epigenetic modifications can impact pathways related to ferroptosis, potentially leading to organ dysfunction. Despite the increasing focus on this relationship, the role of epigenetic regulation in drug development remains largely unexplored. This article explores current research on the interplay between epigenetic regulation and ferroptosis, delving into their regulatory mechanisms and discussing the effects of existing epigenetic modification regulators on diseases. Additionally, we highlight ongoing research on epigenetic factors involved in targeting ferroptosis in cancer, providing new insights for the development of cancer treatments.

Despite advances in treatment, myocardial infarction remains the leading cause of heart failure and death worldwide, and the restoration of coronary blood flow can also cause heart damage. In this study, we found that corosolic acid (CA), also known as plant insulin, significantly protects the heart from ischemia-reperfusion (I/R) injury. In addition, CA can inhibit oxidative stress and improve mitochondrial structure and function in cardiomyocytes. Subsequently, our study demonstrated that CA improved the expression of the mitophagy-related proteins Prohibitin 2 (PHB2), PTEN-induced putative kinase protein-1 (PINK1), and Parkin. Meanwhile, through molecular docking, we found an excellent binding between CA and PHB2 protein. Finally, the knockdown of PHB2 eliminated the protective effect of CA on hypoxia-reoxygenation in cardiomyocytes. Taken together, our study reveals that CA increases mitophagy in cardiomyocytes via the PHB2/PINK1/Parkin signaling pathway, inhibits oxidative stress response, and maintains mitochondrial function, thereby improving cardiac function after I/R.

As a highly aggressive tumor, the pathophysiological mechanism of primary liver cancer has attracted much attention. In recent years, factors such as ferroptosis regulation, lipid peroxidation and metabolic abnormalities have emerged in the study of liver cancer, providing a new perspective for understanding the development of liver cancer. Ferroptosis regulation, lipid peroxidation and metabolic abnormalities play important roles in the occurrence and development of liver cancer. The regulation of ferroptosis is involved in apoptosis and necrosis, affecting cell survival and death. Lipid peroxidation promotes oxidative damage and promotes the invasion of liver cancer cells. Metabolic abnormalities, especially the disorders of glucose and lipid metabolism, directly affect the proliferation and growth of liver cancer cells. Studies of ferroptosis regulation and lipid peroxidation may help to discover new therapeutic targets and improve therapeutic outcomes. The understanding of metabolic abnormalities can provide new ideas for the prevention of liver cancer, and reduce the risk of disease by adjusting the metabolic process. This review focuses on the key roles of ferroptosis regulation, lipid peroxidation and metabolic abnormalities in this process.

This study aims to elucidate the biological functions of ferroptosis-related genes in periodontitis, along with their correlation to tumor microenvironment (TME) features such as immune infiltration. It aims to provide potential diagnostic markers of ferroptosis for clinical management of periodontitis.

Utilizing the periodontitis-related microarray dataset GSE16134 from the Gene Expression Omnibus (GEO) and a set of 528 ferroptosis-related genes identified in prior studies, this research unveils differentially expressed ferroptosis-related genes in periodontitis. Subsequently, a protein-protein interaction network was constructed. Subtyping of periodontitis was explored, followed by validation through immune cell infiltration and gene set enrichment analyses. Two algorithms, randomForest and SVM(Support Vector Machine), were employed to reveal potential ferroptosis diagnostic markers for periodontitis. The diagnostic efficacy, immune correlation, and potential transcriptional regulatory networks of these markers were further assessed. Finally, potential targeted drugs for differentially expressed ferroptosis markers in periodontitis were predicted.

A total of 36 ferroptosis-related genes (30 upregulated, 6 downregulated) were identified from 829 differentially expressed genes between 9 periodontitis samples and the control group. Subsequent machine learning algorithm screening highlighted 4 key genes: SLC1A5(Solute Carrier Family 1 Member 5), SLC2A14(Solute Carrier Family 1 Member 14), LURAP1L(Leucine Rich Adaptor Protein 1 Like), and HERPUD1(Homocysteine Inducible ER Protein With Ubiquitin Like Domain 1). Exploration of these 4 key genes, supported by time-correlated ROC analysis, demonstrated reliability, while immune infiltration results indicated a strong correlation between key genes and immune factors. Furthermore, Gene Set Enrichment Analysis (GSEA) was conducted for the four key genes, revealing enrichment in GO/KEGG pathways that have a significant impact on periodontitis. Finally, the study predicted potential transcriptional regulatory networks and targeted drugs associated with these key genes in periodontitis.

The ferroptosis-related genes identified in this study, including SLC1A5, SLC2A14, LURAP1L, and HERPUD1, may serve as novel diagnostic and therapeutic targets for periodontitis. They are likely involved in the occurrence and development of periodontitis through mechanisms such as immune infiltration, cellular metabolism, and inflammatory chemotaxis, potentially linking the ferroptosis pathway to the progression of periodontitis. Targeted drugs such as flurofamide, L-733060, memantine, tetrabenazine, and WAY-213613 hold promise for potential therapeutic interventions in periodontitis associated with these ferroptosis-related genes.

Liver cancer is the second leading cause of cancer-related death worldwide. However, treatment options, including surgical resection, transplantation, and molecular drug therapies, are of limited effectiveness. Recent studies have demonstrated that suppressing ferroptosis might be a pivotal signal for liver cancer initiation, thus providing a new way to combat liver cancer. Ferroptosis is a distinct form of controlled cell death that differs from conventional cell death routes like apoptosis, necrosis, and pyroptosis. It results from intracellular iron overload, which raises iron-dependent reactive oxygen species. This, in turn, leads to the accumulation of lipid peroxides that further result in oxidative damage to cell membranes, disrupt normal functioning, and ultimately speed up the ferroptosis phenomenon. Ferroptosis regulation is intricately linked to cellular physiological processes, encompassing iron metabolism, lipid metabolism, and the equilibrium between oxygen-free radical reactions and lipid peroxidation. This review intends to summarize the natural compounds targeting ferroptosis in liver cancer to offer new therapeutic ideas for liver cancer. Furthermore, it serves as the foundation for identifying and applying chemical medicines and natural chemicals that target ferroptosis to treat liver cancer efficiently.

Myocardial ischemia-reperfusion injury (MIRI), caused by the initial interruption and subsequent restoration of coronary artery blood, results in further damage to cardiac function, affecting the prognosis of patients with acute myocardial infarction. Ferroptosis is an iron-dependent, superoxide-driven, non-apoptotic form of regulated cell death that is involved in the pathogenesis of MIRI. Ferroptosis is characterized by the accumulation of lipid peroxides (LOOH) and redox disequilibrium. Free iron ions can induce lipid oxidative stress as a substrate of the Fenton reaction and lipoxygenase (LOX) and participate in the inactivation of a variety of lipid antioxidants including CoQ10 and GPX4, destroying the redox balance and causing cell death. The metabolism of amino acid, iron, and lipids, including associated pathways, is considered as a specific hallmark of ferroptosis. This review systematically summarizes the latest research progress on the mechanisms of ferroptosis and discusses and analyzes the therapeutic approaches targeting ferroptosis to alleviate MIRI.

Cancer cells often exhibit defects in the execution of cell death, resulting in poor clinical outcomes for patients with many cancer types. Ferroptosis is a newly discovered form of programmed cell death characterized by intracellular iron overload and lipid peroxidation in the cell membrane. Increasing evidence suggests that ferroptosis is closely associated with a wide variety of physiological and pathological processes, particularly in cancer. Notably, various bioactive natural products have been shown to induce the initiation and execution of ferroptosis in cancer cells, thereby exerting anticancer effects. In this review, we summarize the core regulatory mechanisms of ferroptosis and the multifaceted roles of ferroptosis in cancer. Importantly, we focus on natural products that regulate ferroptosis in cancer cells, such as terpenoids, polyphenols, alkaloids, steroids, quinones, and polysaccharides. The clinical efficacy, adverse effects, and drug-drug interactions of these natural products need to be evaluated in further high-quality studies to accelerate their application in cancer treatment.

Pancreatic cancer (PC) is a fatal human malignancy with a poor prognosis. Corosolic acid (CRA) is a triterpenoid, has been reported to have inhibitory effects on tumor growth. However, the role of CRA on PC has not been explored. Here, we aimed to uncover the molecular mechanisms of CRA in PC progression.

Cell viability, lactate dehydrogenase (LDH) release, cell apoptosis and senescence were detected by cell counting kit-8 (CCK-8), LDH, flow cytometry and senescence associated-β-galactosidase (SA-β-gal) assay. Levels of relevant proteins and oxidative stress (OS) markers were evaluated by Western blot and enzyme-linked immunosorbent assay (ELISA). A xenograft tumor model was established to explore the in vivo effects of CRA on PC.

We found that CRA inhibited PC cell viability and promoted LDH release in a dose-dependent manner, but had no significant effect on human normal pancreatic ductal epithelial cells HPDE6C7. CRA increased OS-induced cell apoptosis and senescence in HAPC and SW1990 cells. And CRA decreased the levels of anti-apoptotic protein Bcl-2, and elevated the expression of pro-apoptotic protein Bax and senescence-associated proteins P21 and P53. Besides, CRA decreased tumor growth in xenograft models. Furthermore, CRA inactivated the Janus kinase-2 (JAK2)/Signal Transducer and Activator of Transcription 3 (STAT3) signaling pathway in HAPC and SW1990 cells. Functional experiments demonstrated that activation of the JAK2/STAT3 pathway by the JAK2 activator coumermycin A1 (C-A1) or the STAT3 activator colivelin (col) reduced the contribution effect of OS, apoptosis and senescence by CRA.

Taken together, our findings indicated that CRA exerted anti-cancer effects in PC by inhibiting the JAK2/STAT3 pathway.

Ferroptosis, first suggested in 2012, is a type of non-apoptotic programmed cell death caused by the buildup of lipid peroxidation and marked by an overabundance of oxidized poly unsaturated fatty acids. During the last decade, researchers have uncovered the formation of ferroptosis and created multiple drugs aimed at it, but due to poor selectivity and pharmacokinetics, clinical application has been hindered. In recent years, biomedical discoveries and developments in nanotechnology have spurred the investigation of ferroptosis nanomaterials, providing new opportunities for the ferroptosis driven tumours treatment. Additionally, hydrogels have been widely studied in ferroptosis because of their unique 3D structure and excellent controllability. By using these biomaterials, it is possible to achieve controlled release and targeted delivery of drugs, thus increasing the potency of the drugs and minimizing adverse effects. Therefore, summarizing the biomedical nanomaterials, including hydrogels, used in ferroptosis for cancer therapy is a must. This article provides an overview of ferroptosis, detailing its properties and underlying mechanisms. It also categorizes and reviews the use of various nanomaterials in ferroptosis, along with relevant explanations and illustrations. In addition, we discuss the opportunities and challenges facing the application of nanomaterials in ferroptosis. Finally, the development prospects of this field are prospected. This review is intended to provide a foundation for the development and application of biomedical nanomaterials in ferroptosis.

Ferroptosis, a unique modality of cell death with mechanistic and morphological differences from other cell death modes, plays a pivotal role in regulating tumorigenesis and offers a new opportunity for modulating anticancer drug resistance. Aberrant epigenetic modifications and posttranslational modifications (PTMs) promote anticancer drug resistance, cancer progression, and metastasis. Accumulating studies indicate that epigenetic modifications can transcriptionally and translationally determine cancer cell vulnerability to ferroptosis and that ferroptosis functions as a driver in nervous system diseases (NSDs), cardiovascular diseases (CVDs), liver diseases, lung diseases, and kidney diseases. In this review, we first summarize the core molecular mechanisms of ferroptosis. Then, the roles of epigenetic processes, including histone PTMs, DNA methylation, and noncoding RNA regulation and PTMs, such as phosphorylation, ubiquitination, SUMOylation, acetylation, methylation, and ADP-ribosylation, are concisely discussed. The roles of epigenetic modifications and PTMs in ferroptosis regulation in the genesis of diseases, including cancers, NSD, CVDs, liver diseases, lung diseases, and kidney diseases, as well as the application of epigenetic and PTM modulators in the therapy of these diseases, are then discussed in detail. Elucidating the mechanisms of ferroptosis regulation mediated by epigenetic modifications and PTMs in cancer and other diseases will facilitate the development of promising combination therapeutic regimens containing epigenetic or PTM-targeting agents and ferroptosis inducers that can be used to overcome chemotherapeutic resistance in cancer and could be used to prevent other diseases. In addition, these mechanisms highlight potential therapeutic approaches to overcome chemoresistance in cancer or halt the genesis of other diseases.

Homocysteine-inducible endoplasmic reticulum protein (HERP) is an endoplasmic reticulum (ER)-resident protein and important for the adaptation of cellular protein homeostasis by ER-associated degradation (ERAD) system. HERP interactors are critical for cellular viability and the reaction to ER stress. To explore the exact mechanisms by which HERP performed the biological functions, we conducted an interaction analysis of HERP protein in HeLa cells by co-immunoprecipitation (Co-IP) and liquid chromatography-mass spectrometer (LC-MS)/MS coupled with label-free quantification (LFQ). Among the interactome results, 123 proteins significantly interacted with HERP, which leads to numerous biological processes including protein import into nucleus, ubiquitin-dependent ERAD pathway, negative regulation of apoptotic process, and protein transport from ER, along with multiple pathways including several diseases, protein processing in ER, fatty acid metabolism, and steroid biosynthesis. Furthermore, we selected several prey proteins from the interactome data and confirmed that HERP interacted with ancient ubiquitous protein 1 (AUP1), Fas-associated factor family member 2 (FAF2), tripartite motif containing 47 (TRIM47), acyl-CoA synthetase long-chain family member 3 (ACSL3), sequestosome 1 (SQSTM1), and poly(rC) binding protein 2 (PCBP2) by Co-IP and confocal microscopy experiments, respectively. Moreover, the expression and location of several interacted proteins were obviously altered in response to ER stress induced by Thapsigargin stimulation and Enterovirus 71 infection. In conclusion, our findings revealed that the vital proteins interacted with HERP to mediate signaling transduction, thus providing novel clues for the mechanisms of HERP associated with ERAD and metabolism in response to ER stress under physiological and pathological conditions.

Malignant transformation from hepatic fibrosis to carcinogenesis may be a therapeutic target for hepatocellular carcinoma (HCC). The aim of this study was to evaluate anti-cancer efficacy of Pien-Tze-Huang (PZH), and to investigate the underlying mechanisms by integrating transcriptional regulatory network analysis and experimental validation.

A diethylnitrosamine (DEN)-induced HCC model in rats was established and used to evaluate the anti-cancer efficacy of PZH. After detecting a transcriptomic profiling, the "disease-related gene-drug effective target" interaction network was constructed, and the candidate targets of PZH against malignant transformation from hepatic fibrosis to HCC were identified and verified in vitro.

PZH effectively alleviated the pathological changes of hepatic fibrosis and cirrhosis, and inhibited tumor formation and growth in DEN-induced HCC rats. Additionally, the administration of PZH reduced the levels of various hepatic function-related serological indicators significantly. Mechanically, a ferroptosis-related SLC7A11-GSH-GPX4 axis might be one of potential targets of PZH against malignant transformation from hepatic fibrosis to HCC. Especially, high SLC7A11 expression may be associated with poor prognosis of HCC patients. Experimentally, the administration of PZH markedly increased the trivalent iron and ferrous ion, suppressed the expression levels of SLC7A11 and GPX4 proteins, and reduced the GSH/GSSG ratio in the liver tissues of DEN-induced HCC rats.

Our data offer an evidence that PZH may effectively improve the hepatic fibrosis microenvironment and prevent the occurrence of HCC through promoting ferroptosis in tumor cells via inhibiting the SLC7A11-GSH-GPX4 axis, implying that PZH may be a potential candidate drug for prevention and treatment of HCC at an early stage.

The identification of mechanisms that underlie the biology of individual tumors is aimed at the development of personalized treatment strategies. Herein, we performed a comprehensive search of genes (termed Supertargets) vital for tumors of particular tissue origin. In so doing, we used the DepMap database portal that encompasses a broad panel of cell lines with individual genes knocked out by CRISPR/Cas9 technology. For each of the 27 tumor types, we revealed the top five genes whose deletion was lethal in the particular case, indicating both known and unknown Supertargets. Most importantly, the majority of Supertargets (41%) were represented by DNA-binding transcription factors. RNAseq data analysis demonstrated that a subset of Supertargets was deregulated in clinical tumor samples but not in the respective non-malignant tissues. These results point to transcriptional mechanisms as key regulators of cell survival in specific tumors. Targeted inactivation of these factors emerges as a straightforward approach to optimize therapeutic regimens.

Corosolic acid is a pentacyclic triterpene acid with hypoglycemic, anti-inflammatory, and anti-cancer effects. However, its potential targets in hepatocellular carcinoma (HCC) are unknown, hindering clinical utilization.

Differentially expressed proteins of the Bel-7404 cell line were identified with tandem mass tag analysis and differentially expressed genes (DEGs) of an HCC TCGA dataset using bioinformatics. Gene functions and pathways were inferred using the DAVID database. Online databases were used to establish P4HA2 expression in HCC (GEPIA2) and its relationship with patient survival (UALCAN and The Human Protein Atlas), the association between P4HA2 expression and immune cell infiltration (TIMER2), and DNA methylation of the P4HA2 gene (MethSurv). Cell proliferation, cell cycle, and cell death were assessed with PI and SYTOX-Green staining, CCK-8, and colony formation assays. Protein expression levels were detected by Western blotting.

A total of 44 differentially expressed proteins and 4498 DEGs were identified. Four genes whose proteins were also found in the differential protein profile but with opposing expressions were selected as candidate targets. The candidate gene prolyl 4-hydroxylase subunit alpha 2 (P4HA2) was recognized as the only potential target due to its high expression in public datasets, association with poor patient survival, and relation to immune cell infiltration in HCC tissues. Moreover, the DNA methylation status in 4 CpG islands of the P4HA2 gene correlated with a poor prognosis. Furthermore, corosolic acid treatment inhibited the proliferation of HCC cell lines Bel-7404 and HepG2 in a dose-dependent manner, caused G2/M phase cell cycle arrest, and promoted cell death. In addition, the treatment reduced P4HA2 protein levels.

Our results indicate that P4HA2 is a potential target of corosolic acid. Thus, they contribute to understanding molecular changes in HCC after corosolic acid treatment and facilitate finding new treatment regimens.

Cancer-associated fibroblasts (CAFs) are a kind of stromal cells in the cholangiocarcinoma (CCA) microenvironment, playing crucial roles in cancer development. However, the potential mechanisms of the interaction between CCA cells and CAFs remain obscure. This work investigated the role of circ_0020256 in CAFs activation. We proved circ_0020256 was up-regulated in CCA. High circ_0020256 expression facilitated TGF-β1 secretion from CCA cells, which activated CAFs via the phosphorylation of Smad2/3. Mechanistically, circ_0020256 recruited EIF4A3 protein to stabilize KLF4 mRNA and upregulate its expression, then KLF4 bound to TGF-β1 promoter and induced its transcription in CCA cells. KLF4 overexpression abrogated the inhibition of circ_0020256 silencing in TGF-β1/Smad2/3-induced CAFs activation. Furthermore, CCA cell growth, migration, and epithelial-mesenchymal transition were favored by CAFs-secreted IL-6 via autophagy inhibition. We also found circ_0020256 accelerated CCA tumor growth in vivo. In conclusion, circ_0020256 promoted fibroblast activation to facilitate CCA progression via EIF4A3/KLF4 pathway, providing a potential intervention for CCA progression.

Ferroptosis is a form of regulated cell death that is initiated by excessive lipid peroxidation that results in plasma membrane damage and the release of damage-associated molecular patterns. In recent years, ferroptosis has gained significant attention in cancer research due to its unique mechanism compared to other forms of regulated cell death, especially caspase-dependent apoptotic cell death. Gastrointestinal (GI) cancer encompasses malignancies that arise in the digestive tract, including the stomach, intestines, pancreas, colon, liver, rectum, anus, and biliary system. These cancers are a global health concern, with high incidence and mortality rates. Despite advances in medical treatments, drug resistance caused by defects in apoptotic pathways remains a persistent challenge in the management of GI cancer. Hence, exploring the role of ferroptosis in GI cancers may lead to more efficacious treatment strategies. In this review, we provide a comprehensive overview of the core mechanism of ferroptosis and discuss its function, regulation, and implications in the context of GI cancers.