Ferroptosis is a type of iron‑dependent cell death characterized by excessive lipid peroxidation and may serve as a potential therapeutic target in cancer treatment. While the mechanisms governing ferroptosis continue to be explored and elucidated, an increasing body of research highlights the significant impact of epigenetic modifications on the sensitivity of cancer cells to ferroptosis. Epigenetic processes, such as DNA methylation, histone modifications and non‑coding RNAs, have been identified as key regulators that modulate the expression of ferroptosis‑related genes. These alterations can either enhance or inhibit the sensitivity of gastrointestinal cancer (GIC) cells to ferroptosis, thereby affecting the fate of GICs. Drugs that target epigenetic markers for advanced‑stage cancer have shown promising results in enhancing ferroptosis and inhibiting tumor growth. This review explores the intricate relationship between epigenetic regulation and ferroptosis in GICs. Additionally, the potential of leveraging epigenetic modifications to trigger ferroptosis in GICs is investigated. This review highlights the importance of further research to elucidate the specific mechanisms underlying epigenetic control of ferroptosis and to advance the development of novel therapeutic approaches.

One of the most common tumors is hepatocellular carcinoma (HCC), and the prognosis for late-stage HCC is still not good. It is anticipated that improved outcomes would result from a deeper comprehension of the pathophysiology of HCC. Ferroptosis as a new discovered cell death type is linked to the progression of HCC and may be crucial for its detection, prevention, therapy, and prognosis. Numerous studies suggest that epigenetic alterations mediated by non-coding RNAs (ncRNA) might influence cancer cell susceptibility to ferroptosis. This study elucidates the processes of ferroptosis and delineates the paths by which ncRNAs influence HCC by modulating ferroptosis. Furthermore, it offers significant insights into ferroptosis-associated ncRNAs, intending to discover novel therapeutic approaches for HCC. It also explores innovative concepts for the future use of ncRNA-based ferroptosis-targeted therapeutics.

Hepatocellular carcinoma (HCC), the predominant kind of liver cancer, continues to be a significant contributor to cancer-related deaths globally, influenced by intricate molecular processes and strong resistance to existing chemotherapy. Iron-dependent lipid peroxidation induces ferroptosis, a controlled form of cell death that plays a crucial role in inhibiting tumor growth and treatment resistance in HCC. Recent research has shown that epigenetic modifications, such as DNA methylation, histone modifications, regulation by non-coding RNAs (ncRNAs), and post-translational modification (PTM) like ubiquitination, phosphorylation, acetylation, and methylation, play a crucial role in fine-tuning ferroptosis. These alterations alter the structure of chromatin, gene expression, and protein function, thereby affecting cancer cells' fate. This review emphasizes the complex functions of epigenetic and post-translational alterations in controlling ferroptosis, providing valuable insights into their potential as therapeutic targets in HCC. The unraveling of these pathways offers a significant opportunity for novel therapies targeted at surmounting drug resistance and enhancing patient outcomes in liver cancer.

Hepatocellular carcinoma (HCC) is the most prevalent form of primary liver cancer, associated with high morbidity and mortality worldwide. Despite advancements in diagnostic methods and systemic treatments, including tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs), the development of drug resistance remains a significant challenge in HCC management. Traditional treatments such as surgical resection and transarterial chemoembolization offer limited efficacy, especially in advanced stages. Although novel therapies like lenvatinib, sorafenib, regorafenib, and ICIs have shown promise, their effectiveness is often hindered by primary and acquired resistance, leading to poor long-term survival outcomes. This review focuses on the molecular mechanisms underlying resistance to targeted therapies and immunotherapies in HCC. Key factors contributing to resistance include alterations in the tumor microenvironment (TME), immune evasion, hypoxia, changes in cellular metabolism, and genetic mutations. Additionally, molecular players such as ferroptosis, autophagy, apoptosis, endoplasmic reticulum stress, ABC transporters, and non-coding RNAs(ncRNAs) are discussed as contributors to drug resistance. Understanding these mechanisms is critical for the development of novel therapeutic strategies aimed at overcoming resistance, improving patient outcomes, and ultimately enhancing survival rates in HCC patients.

Long non-coding RNAs (lncRNAs) play critical roles in the process of lung tissue injury and repair which abnormal repair leads to disease including fibrosis, yet the physiopathology remains elusive. Here, we identified the lncRNA SYISL as a key regulator that is markedly upregulated in idiopathic pulmonary fibrosis (IPF) patients and bleomycin (BLM)-induced murine fibrotic lungs. Inhibition of SYISL significantly attenuates TGF-β1-driven fibroblast myofibroblast transition (FMT), a process confers to tissue injury repair and regeneration. Which demonstrates SYISL interaction with miR-23a function as a potent suppressor of fibrotic activation. Mechanistically, SYISL acts as a competing endogenous RNA (ceRNA) that directly binds miR-23a, thereby derepressing TRIO and F-actin binding protein (TRIOBP) via targeting its 3' untranslated region (UTR). Knockdown of TRIOBP amplifies the anti-fibrotic effects of miR-23a mimics while abolishing the pro-fibrotic activity of miR-23a inhibitors, establishing TRIOBP as a downstream effector of the SYISL/miR-23a axis. In vivo, intratracheal delivery of SYISL-targeting shRNA via adeno-associated virus (AAV) robustly reduces collagen deposition, hydroxyproline content, and expression of fibrotic markers in BLM-induced mice. Our findings elucidate a lncRNA-driven regulatory circuit in which SYISL promotes pulmonary fibrosis by sequestering miR-23a to elevate TRIOBP expression, nominating this axis as a novel therapeutic target for IPF.

The most prevalent primary hepatic cancer, hepatocellular carcinoma (HCC), has a bad prognosis. HCC prevalence and related deaths have increased in recent decades. Food and Drug Administration (FDA) has licensed Sorafenib as a first-line treatment for individuals with advanced HCC. Despite this, some clinical studies indicate that a significant percentage of liver cancer patients exhibit insensitivity to sorafenib. Furthermore, the overall effectiveness of sorafenib is far from adequate, and the number of patients who benefit from therapy is low. In recent years, many researchers have focused on the mechanisms underlying sorafenib resistance. Acquired resistance to sorafenib in HCC cells has been reported to be facilitated by dysregulation of signal transducer and activator of transcription 3 (STAT3) activation, angiogenesis, autophagy, hypoxia-induced pathways, epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs), ferroptosis, and non-coding RNAs (ncRNAs). Recent clinical trials, including comparisons of sorafenib with immune checkpoint inhibitors like tislelizumab, have shown promise in improving patient outcomes. Additionally, combination therapies targeting complementary pathways are under investigation to overcome resistance and enhance treatment efficacy. The limitation of Sorafenib's effectiveness has been partially but not completely clarified. Furthermore, while certain regimens have demonstrated positive results, more clinical trials are required to confirm them. Future research should focus on identifying predictive biomarkers for therapy response, targeting the tumor microenvironment, and exploring novel therapeutic agents and personalized medicine strategies. A deeper understanding of these mechanisms will be essential for developing more effective therapeutic approaches and improving the prognosis of patients with advanced HCC. This article discusses strategies that may be employed to enhance the success of treatment and summarizes new research on the possible pathways that lead to sorafenib resistance.

The emergence of resistance to antitumor drugs in cancer cells presents a notable obstacle in cancer therapy. Metabolic reprogramming is characterized by enhanced glycolysis, disrupted lipid metabolism, glutamine dependence and mitochondrial dysfunction. In addition to promoting tumor growth and metastasis, metabolic reprogramming mediates drug resistance through diverse molecular mechanisms, offering novel opportunities for therapeutic intervention. Non‑coding RNAs (ncRNAs), a diverse class of RNA molecules that lack protein‑coding function, represent a notable fraction of the human genome. Due to their distinct expression profiles and multifaceted roles in various cancers, ncRNAs have relevance in cancer pathophysiology. ncRNAs orchestrate metabolic abnormalities associated with drug resistance in cancer cells. The present review provides a comprehensive analysis of the mechanisms by which metabolic reprogramming drives drug resistance, with an emphasis on the regulatory roles of ncRNAs in glycolysis, lipid metabolism, mitochondrial dysfunction and glutamine metabolism. Furthermore, the present review aimed to discuss the potential of ncRNAs as biomarkers for predicting chemotherapy responses, as well as emerging strategies to target ncRNAs that modulate metabolism, particularly in the context of combination therapy with anti‑cancer drugs.

Myocardial ischemia-reperfusion injury (MIRI) is a common complication of cardiovascular disease and its pathogenesis remains unclear. ETS1 (E26 transformation-specific sequence-1) is a transcription factor that plays an important regulatory role in vascular development and generation. Therefore, this study aims to explore the role of ETS1 in MIRI and its potential molecular mechanisms. An OGD/R-induced H9C2 cardiomyocyte model was established, and cell viability was determined by CCK8 and changes in SOD, MDA and GSH levels by ELISA; expression of ETS1, PIM3 and ferroptosis-related indices were determined by immunofluorescence, Western blot and qPCR; at the same time, a mouse MIRI model was established to assess changes in myocardial injury and changes in ferroptosis after knockdown of ETS1. In the OGD/R-induced H9C2 cell model, cell viability was significantly lower than that of the control group, and the level of intracellular ferroptosis was significantly enhanced. Further research has revealed that in the OGD/R-induced H9C2 model, the expression of ETS1 is significantly upregulated. Knockdown of ETS1 can reverse the myocardial cell injury induced by OGD/R. Mechanistically, ETS1 promotes the progression of MIRI by targeting and regulating PIM3, thereby exacerbating ferroptosis. Additionally, in a mouse MIRI model, the knockdown of ETS1 significantly enhances the expression of GPX4, SLC7A11, and FTH1 proteins, inhibits the ferroptosis process, and thereby improves MIRI in mice. The research results indicate that ETS1 promotes the MIRI process through regulating ferroptosis of cardiomyocytes mediated by PIM3. This discovery provides important scientific evidence for further elucidating the mechanisms underlying MIRI and developing therapeutic strategies.

Ferroptosis is a novel form of cell death characterised by iron overload and lipid peroxidation. It is closely associated with many diseases, including cardiovascular diseases, tumours, and neurological diseases. The use of natural chemicals to modulate ferroptosis is of great concern because of the critical role ferroptosis plays in disease. The main active ingredient in green tea is epigallocatechin gallate (EGCG), which is the most abundant catechin in green tea. EGCG shows a wide range of biological and therapeutic effects in various diseases, including anti-inflammatory, antioxidant, anticancer, and cardioprotective.

The purpose of this article is to summarise the existing information on the relationship between EGCG and ferroptosis.

Articles related to EGCG and ferroptosis were searched in PubMed and Web of Science databases, and the literature was analysed.

EGCG could improve ferroptosis-related diseases and affect the development of ferroptosis by regulating the nuclear factor erythroid 2-related factor 2, autophagy, microRNA, signal transducer and activator of transcription 1, and protein kinase D1 signalling pathways.

Hepatocellular carcinoma (HCC) is a common malignant tumor with high morbidity and mortality, as well as poor prognosis. Therefore, it is imperative to explore alternative therapeutic targets for HCC treatment. Ferroptosis and cuproptosis have recently been identified as metal-dependent cell death mechanisms that play significant roles in HCC treatment. This study identified potential cross-talk between ferroptosis and cuproptosis, including the common hub glutathione, common site of occurrence, mitochondria, shared epigenetic modification mode, RNA N6 methyladenosine modification, mutual inhibitor, nuclear factor erythroid 2-related factor 2, and dual regulator, p53. These findings provide a theoretical foundation for the joint induction of HCC cell death and effective inhibition of HCC progression. However, some immune cells are susceptible to ferroptosis or cuproptosis, which may impair or enhance anti-cancer immune function. We propose strategies to target specific targets molecules such as tripartite motif containing 25, ferroptosis suppressor protein 1, and peroxisome proliferator-activated receptor gamma or exploit the unique acidic environment surrounding cancer cells to precisely induce ferroptosis in cancer cells. This approach aims to advance the development of precision medicine for HCC treatment.

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide. Despite extensive research, the mechanistic underpinnings driving CRC progression remain largely unknown. As a fundamental component of the brush border cytoskeleton, villin-1 (VIL1) acts as a marker for intestinal cell differentiation and maturation. Through a comprehensive transcriptomics analysis of eight studies (total sample: n = 1952), we consistently observed significant upregulation of VIL1 expression in CRC tumors compared with adjacent normal tissue. In our independent cohort, this notable upregulation has been further validated at both mRNA and protein levels in colon tumor tissues, relative not only to adjacent normal tissue but also to normal controls. Our data show that VIL1 promotes proliferation and migration while inhibiting apoptosis. Conversely, knockout of VIL1 suppresses proliferation and migration while inducing apoptosis. Mechanistically, we reveal that knocking out VIL1 activates ferroptosis and inhibits the migration of CRC cells, while overexpressing VIL1 yields the opposite effects, and vice versa. Additionally, VIL1 binds to Nuclear factor NF-kappa-B p105 subunit (NF-κB) and controls NF-κB expression. In vivo, overexpressing VIL1 inhibits ferroptosis, and induces the expression of NF-κB and lipocalin 2 (LCN2), thereby promoting CRC tumor growth. Thus, we have identified the VIL1/NF-κB axis as a pivotal regulator of CRC progression through ferroptosis modulation, unveiling VIL1 as a promising therapeutic target for CRC treatment via ferroptosis. Our study offers novel avenues for exploring the therapeutic potential of ferroptosis in CRC management, emphasizing the high potential of VIL1 in regulating colorectal tumorigenesis.

Hepatocellular carcinoma (HCC) is a major type of liver cancer and an important cause of cancer death. It has been reported that the hepatocyte death plays an important role in HCC. Ferroptosis is an iron-dependent programmed cell death characterized by the accumulation of free iron and lipid peroxidation. A series of studies have shown that ferroptosis contributes to the occurrence and development of HCC. MicroRNAs (miRNAs) are non-coding RNAs with a length of approximately 222 nt. In recent years, miRNAs have been shown to participate in regulating ferroptosis to play a vital role in HCC, but the related mechanisms are not fully understood. This review summarized the current understanding of ferroptosis, as well as the biogenesis and function of miRNAs, and focused on the role of miRNAs regulation of ferroptosis in HCC, with the hope of providing new targets and ideas for the treatment of HCC.

The high mortality rate from hepatocellular carcinoma (HCC) is due primarily to challenges in early diagnosis and the development of drug resistance in advanced stages. Many first-line chemotherapeutic drugs induce ferroptosis, a form of programmed cell death dependent on ferrous iron-mediated oxidative stress, suggesting that drug resistance and ensuing tumor progression may in part stem from reduced ferroptosis. Since circular RNAs (circRNAs) have been shown to influence tumor development, we examined whether specific circRNAs may regulate drug-induced ferroptosis in HCC. Through circRNA sequencing, we identified a novel hsa_circ_0000195 (circTTC13) that is overexpressed in HCC tissues. This overexpression is linked to higher tumor grade, more advanced tumor stage, decreased ferroptosis, and poorer overall survival. Overexpression of CircTTC13 in HCC cell lines and explant tumors was associated with increased proliferation rates, enhanced metastatic capacity, and resistance to sorafenib, while also inhibiting ferroptosis. Conversely, circTTC13 silencing reduced malignant characteristics and promoted ferroptosis. In silico analysis, luciferase assays, and fluorescence in situ hybridization collectively demonstrated that circTTC13 directly targets and reduces miR-513a-5p expression, which in turn leads to the upregulation of the negative ferroptosis regulator SLC7A11. Moreover, the inhibition of SLC7A11 mirrored the effect of circTTC13 knockdown, whereas ferroptosis inhibition mimicked the effect of circTTC13 overexpression. Both circTTC13 and SLC7A11 were highly expressed in drug-resistant HCC cells, and circTTC13 silencing induced ferroptosis and reversed sorafenib resistance in explant tumors. These findings identify circTTC13 as a critical driver of HCC progression and resistance to drug-induced ferroptosis via upregulation of SLC7A11. The cicTTC13/miR-513a-5p/SLC7A11 axis represents a potential therapeutic target for HCC.

Diet composition is important for health, especially during critical periods such as pre-gestation (P), gestation (G), or lactation (S), due to its potential impact not only on the mother but on the offspring. The Mediterranean diet includes many healthy foods rich in fiber and/or polyphenols, such as whole grains, fruits, vegetables, beans, and nuts. The present preclinical study assesses the impact of a diet rich in fiber and polyphenols (HFP diet) during one of those three periods (P, G, or S, three weeks each) on the rat gene expression of the small intestine obtained at the end of the lactation period.

This analysis was performed by the mRNA two step PCR amplification by random primers and poly-T, followed by library generation and HiSeq X-Ten Illumina sequencing (Seqplexing), and further confirmed by Real time PCR and ELISA.

The results showed a broad number of genes significantly modulated after the HFP diet compared to the reference diet, with a higher number of genes modulated when the supplementing period was closer to the analysis day (S > G > P). Notably, genes involved in immune signaling, intestinal absorption, and cell growth were among those more significantly affected by the HFP dietary intervention. The HFP diet influenced the expression of key genes such as ferritin, fatty acid synthase, apelin, and complement proteins, among others. There was a unique gene modified in all the intervention periods (Family with Sequence Similarity 117 Member A, Fam117A, which codifies a protein with unknown function), indicating that this molecule may participate critically in the effects induced by fiber and polyphenols during these periods.

Overall, in rats, the influence of diet for a three-week period around birth is able to modulate the intestinal gene expression, and consequently, maternal health, which can eventually have an indirect impact on the offspring.

Ferroptosis is an iron-dependent form of programmed cell death induced by lipid peroxidation. This process is regulated by signaling pathways associated with redox balance, iron metabolism, and lipid metabolism. Cancer cells' increased iron demand makes them especially susceptible to ferroptosis, significantly influencing cancer development, therapeutic response, and metastasis. Recent findings indicate that cancer cells can evade ferroptosis by downregulating key signaling pathways related to this process, contributing to drug resistance. This underscores the possibility of modulating ferroptosis as an approach to counteract drug resistance and enhance therapeutic efficacy. This review outlines the signaling pathways involved in ferroptosis and their interactions with cancer-related signaling pathways. We also highlight the current understanding of ferroptosis in cancer drug resistance, offering insights into how targeting ferroptosis can provide novel therapeutic approaches for drug-resistant cancers. Finally, we explore the potential of ferroptosis-inducing compounds and examine the challenges and opportunities for drug development in this evolving field.

Fuchs endothelial corneal dystrophy (FECD) is the leading cause of keratoplasty without drug treatment. Research indicated that oxidative stress and lipid peroxidation play significant roles in FECD. However, the underlying pathogenesis and potential treatment remain poorly understood. We analyzed the mRNA expression of FECD using the GEO database (GSE171830). Utilizing the STRING database and Cytoscape's MCODE plugin, we identified hub genes that intersect with ferroptosis-related genes listed in FerrDb. FECD cell and animal models were developed, induced by Ultraviolet A exposure. We assessed ferroptosis by measuring GPX4 expression and ROS fluorescence intensity. MiR-23a-3p was compared between FECD model and normal control, and the target gene PTEN was confirmed through Western blot and dual-luciferase reporter assays. Treatment with PTEN, PI3K, Akt, and mTOR inhibitors provided insights into the role of the PTEN/PI3K/Akt/mTOR pathway in FECD model. Corneal endothelium and cellular structure were evaluated before and after delivery of miR-23a-3p. Bioinformatics analysis of the GSE171830 revealed the top five hub genes: TP53, PTEN, EGFR, EPAS1, and IL-1β. Ferroptosis is the predominant mechanism in FECD pathogenesis, distinct from apoptosis and necrosis. We uncovered a protective role for miR-23a-3p in corneal endothelial cells (CEnCs), mitigating ferroptosis by downregulating PTEN. Corroborating this, bpV (a PTEN inhibitor) was found to attenuate ferroptosis in CEnCs. Mechanistically, PTEN inhibition coupled with sustained PI3K/Akt/mTOR pathway activation emerged as a protective strategy against ferroptosis in CEnCs. Ferroptosis contributes to FECD pathogenesis, and targeted delivery of miR-23a-3p as a ferroptosis inhibitor may offer therapeutic potential by regulating PTEN/PI3K/Akt/mTOR signaling.

To explore a causal relationship between ferroptosis-related gene heat shock protein A5 (HSPA5) and hepatocellular carcinoma (HCC).

A two-sample Mendelian randomization (MR) design was employed to evaluate the causal relationships among HSPA5, regulatory T cells (Tregs), and HCC. Single nucleotide polymorphisms (SNPs) associated with HSPA5, Tregs and HCC were selected as instrumental variables through publicly available genome-wide association studies (GWAS) databases. MR analysis was used to assess the direct effect of HSPA5 on HCC, followed by two-step MR to analyze the potential mediating role of Tregs. Reverse MR analysis was conducted with HCC as the exposure and HSPA5 as the outcome. Inverse variance weighting was the primary method for testing causal associations in all MR analyses. Robustness of the results was confirmed through MR-Egger, weighted median, weighted mode, and simple mode methods. Heterogeneity of instrumental variables was evaluated using Cochrane's Q statistic, while pleiotropy was tested by MR-Egger intercept and MR-PRESSO, with leave-one-out sensitivity analysis performed for robustness. Data from The Cancer Genome Atlas (TCGA) and Human Protein Atlas (HPA) were utilized to verify the expression levels of HSPA5 in HCC tissues and its correlation with Tregs to reveal the interaction mechanisms between HSPA5 and Tregs in HCC progression and their relationship with patient prognosis.

MR analysis showed a positive correlation between elevated HSPA5 expression and HCC risk (all P<0.01), while reverse MR analysis found no statistically significant association between HCC and HSPA5 (P>0.05). HSPA5 expression was significantly correlated with Tregs function (all P<0.05), and the enrichment of Tregs in HCC microenvironment was positively associated with HCC progression (all P<0.05). Mediation analysis indicated that Tregs accounted for 5.00% and 7.45% of the mediation effect between HSPA5 and HCC. TCGA and HPA database analysis revealed that both HSPA5 mRNA and protein expression levels were higher in HCC tissues compared to normal tissues, and high HSPA5 expression was significantly associated with poor prognosis. Immune infiltration analysis confirmed a significant positive correlation between HSPA5 and Tregs, with high Tregs infiltration closely related to HCC progression.

Elevated HSPA5 expression is significantly associated with HCC development and poor prognosis. HSPA5 may promote HCC progression by regulating the function of Tregs in the tumor microenvironment.

The identification of ferroptosis represents a pivotal advancement in the field of cell death research, revealing an entirely novel mechanism of cellular demise and offering new insights into the initiation, progression, and therapeutic management of various diseases. Ferroptosis is predominantly induced by intracellular iron accumulation, lipid peroxidation, or impairments in the antioxidant defense system, culminating in membrane rupture and consequent cell death. Studies have associated ferroptosis with a wide range of diseases, and by enhancing our comprehension of its underlying mechanisms, we can formulate innovative therapeutic strategies, thereby providing renewed hope for patients.

Hepatocellular carcinoma (HCC) is the most prevalent malignant tumor, characterized by a poor prognosis. In recent decades, both the incidence and mortality rates of HCC have risen sharply. Sorafenib has emerged as the first conventional drug approved by the US Food and Drug Administration for first-line treatment in advanced HCC patients due to its favorable safety profile. However, its effectiveness is severely hindered by acquired drug resistance, which leads to only approximately 30% of HCC patients benefited from sorafenib therapy. Sorafenib resistance involves various mechanisms that inhibit cellular uptake of iron and reactive oxygen species (ROS). Consequently, ferroptosis a novel form of cell death contingent upon the accumulation of intracellular iron and ROS plays a critical role in mediating sorafenib resistance through the Hippo YAP pathway or Keap1-Nrf2 system. This review aimed to comprehensively elucidate the mechanisms underlying sorafenib resistance in HCC, particularly focusing on ferroptosis and its pathways, to provide valuable insights into targeting ferroptosis or its pathways for sorafenib-resistant HCC treatment.

This study aims to improve the solubility and the toxicity of Bufonis venenum, and finally enhance the therapeutic outcomes of hepatocellular carcinoma (HCC).

The cholesterol-free liposomes simultaneously encapsulate bufadienolides and indolealkylamines (Non-Cholesterol-Bufonis Venenum Extract-Liposome, Non-Chol-BVE-LP) was prepared by the thin-film evaporation technique. In vitro, the cytotoxicity, cell apoptosis study, cellular uptake and hemolysis studies were evaluated in HepG2 cells. In vivo, the biodistribution and anti-tumor activity studies were conducted in BALB/C mice with HepG2 cells.

The liposomes showed good size distribution, encapsulation efficiency drug loading capacity and slower drug release. Non-Chol-BVE-LP had higher cytotoxicity on HepG2 cells and induced more apoptosis on HepG2 Cells compared with BVE. In addition, the liposomes could accumulate in tumor by passive targeting, thus facilitating the anti-tumor effects. In vivo, Non-Chol-BVE-LP showed equivalent anti-tumor efficacy to the first-line anti-HCC drug sorafenib.

The study provided new ideas for the development and clinical application of Bufonis venenum related formulation and offered new drug for the treatment of HCC.

Hepatocellular carcinoma (HCC) is a common malignancy with a poor prognosis. The recommended treatment of unresectable HCC involves targeted therapy, for example sorafenib, combined with immunotherapy. A recent article reported that sorafenib could induce ferroptosis escape in HCC. Brusatol is a novel Nrf2 inhibitor that takes effects in various diseases. In our study, we aimed to identify whether the addition of Brusatol to sorafenib could reverse ferroptosis escape in Huh7 cells.

The cultured Huh7 cells treated by sorafenib with or without Brusatol addition were harvested for ferroptotic phenotype experiments and ferroptosis-related markers such as GPX4 and SLC7A11 were detected. In vivo experiments were conducted to discover the effect of Brusatol in combination with sorafenib in liver tumor bearing mice. Mechanism signaling pathways were detected by RNA-sequencing.

Brusatol alone could induce Huh7 cell death and sorafenib could moderately mediate Huh7 cell ferroptosis by paradoxically inhibiting GPX4. However, sorafenib simultaneously upregulates Nrf2 signaling in Huh7 cells fighting against ferroptosis to result in sorafenib resistance. The addition of Brusatol could potentiate ferroptosis in Huh7 cells through downregulating Nrf2 and the downstream HO-1 and NQO1, thus enhancing the efficacy of sorafenib, which could be reversed by ferrostatin-1 treatment.

In conclusion, Brusatol improves the efficacy of sorafenib by inducing ferroptosis via hindering Nrf2 signaling activation in HCC.

Hepatocellular carcinoma (HCC) is one of the most common malignances in the world, with high morbidity and mortality. Due to the hidden onset of symptoms, there are huge obstacles in early diagnosis, recurrence, metastasis and drug resistance. Although great strides have been made in the treatment of HCC, effective treatment options are still limited and achieving longer survival for patients remains urgent. Ferroptosis is a novel type of programmed cell death that is mainly caused by iron-dependent oxidative damage. With further investigations, ferroptosis has been proved to be associated with the occurrence and development of various tumors. This article reviews the regulatory mechanism and signal transduction pathways of ferroptosis, investigates the complex relationship between autophagy, sorafenib resistance and immunotherapy with ferroptosis involved in HCC, providing new ideas and directions for the treatment of HCC.

Ferroptosis, a form of iron-dependent regulated cell death, is characterized by the accumulation of lipid peroxides and distinctive morphological features. Moreover, the reduction of intracellular antioxidant enzyme expression or activity, specifically glutathione peroxidase 4 (GPX4) results in activation of the endogenous pathway of ferroptosis. In this review, we aimed to explore the intricate interplay between microRNAs (miRNAs) and ferroptosis, shedding light on its implications in various disease pathologies. This review delves into the role of miRNAs in modulating key regulators of ferroptosis, including genes involved in iron metabolism, lipid peroxidation, and antioxidant defenses. Furthermore, the potential of targeting miRNAs for therapeutic interventions in ferroptosis-related diseases, such as cancer, neurodegenerative disorders, and ischemia/reperfusion injury, is highlighted.

This review focuses on the role and underlying mechanisms of mitotic catastrophe (MC) in the regulation of drug resistance in hepatocellular carcinoma (HCC). HCC is one of the leading causes of cancer-related mortality worldwide, posing significant treatment challenges due to its high recurrence rates and drug resistance. Research suggests that MC, as a mechanism of cell death, plays a crucial role in enhancing the efficacy of HCC treatment by disrupting the replication and division mechanisms of tumor cells. The present review summarizes the molecular mechanisms of MC and its role in HCC drug resistance and explores the potential of combining MC with existing cancer therapies to improve treatment outcomes. Future research should focus on the in-depth elucidation of the molecular mechanisms of MC and its application in HCC therapy, providing new insights for the development of more effective treatments.

Prostate apoptosis response protein-4 (PAR-4) is considered a tumor suppressor. However, the role of PAR-4 in hepatocellular carcinoma (HCC) has rarely been reported. The study explores the role of PAR-4 in the malignant behaviors of HCC cells.

TCGA database was applied to analyze the expression of PAR-4 in HCC. Evaluated PAR-4 relationship with clinical parameters and prognosis by tissue microarray; expression of STAT3, p-STAT3, Src and Ras was detected by Western blotting or laser confocal microscopy. Cell scratch and flow cytometry assays were used to observe IL-6 regulation of the malignant behaviors of HCC cells. The tumorigenic potential of HCC cells in vivo was evaluated in a nude mouse tumor model.

Analysis indicated that the expression of PAR-4 in HCC tissues was significantly higher than that in normal liver tissues; and PAR-4 interacted with STAT3. KEGG analysis showed that PAR-4 plays a role in the Janus kinase (JAK)/STAT signaling pathway. The positive expression rate of PAR-4 in HCC tissues was significantly higher than that in adjacent tissues. Positive correlation between IL-6 and PAR-4 expression in the HCC tissues. Exogenous IL-6 significantly promoted the proliferation and migration of HCC cells and up-regulated the expression of PAR-4 and p-STAT3 in HCC cells. Interference of the expression of PAR-4 could reduce the malignant behaviors of HCC cells and inhibit tumorigenesis in a nude mouse tumor model.

PAR-4 expression is positively correlated with HCC; PAR-4 promotes malignant behavior of HCC cells mediated by the IL-6/STAT3 signaling pathway.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. Tumor immune microenvironment (TIME), angiogenesis, epithelial-mesenchymal transformation (EMT), invasion, metastasis, metabolism, and drug resistance are the main factors affecting the development and treatment of tumors. MiRNAs play crucial roles in almost all major cellular biological processes. Studies have been carried out on miRNAs as biomarkers and therapeutic targets. Their dysregulation contributes to the progression and prognosis of HCC. This review aims to explore the molecular cascades and corresponding phenotypic changes caused by aberrant miRNA expression and their regulatory mechanisms, summarize and analyze novel biomarkers from somatic fluids (plasma/serum/urine), and highlight the latent capacity of miRNAs as therapeutic targets.

Hepatocellular carcinoma (HCC) is the sixed most common malignant tumor in the world. The study for HCC is mired in the predicament confronted with the difficulty of early diagnosis and high drug resistance, the survival rate of patients with HCC being low. Ferroptosis, an iron-dependent cell death, has been discovered in recent years as a cell death means with tremendous potential to fight against cancer. The in-depth researches for iron metabolism, lipid peroxidation and dysregulation of antioxidant defense have brought about tangible progress in the firmament of ferroptosis with more and more results showing close connections between ferroptosis and HCC. The potential role of ferroptosis has been widely used in chemotherapy, immunotherapy, radiotherapy, and nanotherapy, with the development of various new drugs significantly improving the prognosis of patients. Based on the characteristics and mechanisms of ferroptosis, this article further focuses on the main signaling pathways and promising treatments of HCC, envisioning that existing problems in regard with ferroptosis and HCC could be grappled with in the foreseeable future.

Ferroptosis, a unique type of regulated cell death plays a vital role in inhibiting tumour malignancy and has presented new opportunities for treatment of therapy in hepatocellular carcinoma. Accumulating studies indicate that epigenetic modifications by non-coding RNAs, including microRNAs, long noncoding RNAs, and circular RNAs, can determine cancer cell vulnerability to ferroptosis in HCC. The present review first summarize the updated core molecular mechanisms of ferroptosis. We then provide a concised overview of epigenetic modification of ferroptosis in HCC. Finally, we review the recent progress in understanding of the ncRNA-mediated regulated mechanisms on ferroptosis in HCC. The review will promote our understanding of the ncRNA-mediated epigenetic regulatory mechanisms modulating ferroptosis in malignancy of HCC, highlighting a novel strategies for treatment of HCC through targeting ncRNA-ferroptosis axis.

Ferroptosis is a type of cell death that plays a remarkable role in the growth and advancement of malignancies including hepatocellular carcinoma (HCC). Non-coding RNAs (ncRNAs) have a considerable impact on HCC by functioning as either oncogenes or suppressors. Recent research has demonstrated that non-coding RNAs (ncRNAs) have the ability to control ferroptosis in HCC cells, hence impacting the advancement of tumors and the resistance of these cells to drugs. Autophagy is a mechanism that is conserved throughout evolution and plays a role in maintaining balance in the body under normal settings. Nevertheless, the occurrence of dysregulation of autophagy is evident in the progression of various human disorders, specifically cancer. Autophagy plays dual roles in cancer, potentially influencing both cell survival and cell death. HCC is a prevalent kind of liver cancer, and genetic mutations and changes in molecular pathways might worsen its advancement. The role of autophagy in HCC is a subject of debate, as it has the capacity to both repress and promote tumor growth. Autophagy activation can impact apoptosis, control proliferation and glucose metabolism, and facilitate tumor spread through EMT. Inhibiting autophagy can hinder the growth and spread of HCC and enhance the ability of tumor cells to respond to treatment. Autophagy in HCC is regulated by several signaling pathways, such as STAT3, Wnt, miRNAs, lncRNAs, and circRNAs. Utilizing anticancer drugs to target autophagy may have advantageous implications for the efficacy of cancer treatment.

Hepatocellular carcinoma (HCC) presents a significant global health burden, with alarming statistics revealing its rising incidence and high mortality rates. Despite advances in medical care, HCC treatment remains challenging due to late-stage diagnosis, limited effective therapeutic options, tumor heterogeneity, and drug resistance. MicroRNAs (miRNAs) have attracted substantial attention as key regulators of HCC pathogenesis. These small non-coding RNA molecules play pivotal roles in modulating gene expression, implicated in various cellular processes relevant to cancer development. Understanding the intricate network of miRNA-mediated molecular pathways in HCC is essential for unraveling the complex mechanisms underlying hepatocarcinogenesis and developing novel therapeutic approaches. This manuscript aims to provide a comprehensive review of recent experimental and clinical discoveries regarding the complex role of miRNAs in influencing the key hallmarks of HCC, as well as their promising clinical utility as potential therapeutic targets.

The development of drug resistance remains a major challenge in cancer treatment. Ferroptosis, a unique type of regulated cell death, plays a pivotal role in inhibiting tumour growth, presenting new opportunities in treating chemotherapeutic resistance. Accumulating studies indicate that epigenetic modifications by non-coding RNAs (ncRNA) can determine cancer cell vulnerability to ferroptosis. In this review, we first summarize the role of chemotherapeutic resistance in cancer growth/development. Then, we summarize the core molecular mechanisms of ferroptosis, its upstream epigenetic regulation, and its downstream effects on chemotherapeutic resistance. Finally, we review recent advances in understanding how ncRNAs regulate ferroptosis and from such modulate chemotherapeutic resistance. This review aims to enhance general understanding of the ncRNA-mediated epigenetic regulatory mechanisms which modulate ferroptosis, highlighting the ncRNA-ferroptosis axis as a key druggable target in overcoming chemotherapeutic resistance.

With aging and the increasing incidence of obesity, nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide. NAFLD mainly includes simple hepatic steatosis, nonalcoholic steatohepatitis (NASH), liver fibrosis and hepatocellular carcinoma (HCC). An imbalance in hepatic iron homeostasis is usually associated with the progression of NAFLD and induces iron overload, reactive oxygen species (ROS) production, and lipid peroxide accumulation, which leads to ferroptosis. Ferroptosis is a unique type of programmed cell death (PCD) that is characterized by iron dependence, ROS production and lipid peroxidation. The ferroptosis inhibition systems involved in NAFLD include the solute carrier family 7 member 11 (SLC7A11)/glutathione (GSH)/glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1)/coenzyme Q10 (CoQ10)/nicotinamide adenine dinucleotide phosphate (NADPH) regulatory axes. The main promotion system involved is the acyl-CoA synthetase long-chain family (ACSL4)/arachidonic lipoxygenase 15 (ALOX15) axis. In recent years, an increasing number of studies have focused on the multiple roles of iron homeostasis imbalance and ferroptosis in the progression of NAFLD. This review highlights the latest studies about iron homeostasis imbalance- and ferroptosis-associated NAFLD, mainly including the physiology and pathophysiology of hepatic iron metabolism, hepatic iron homeostasis imbalance during the development of NAFLD, and key regulatory molecules and roles of hepatic ferroptosis in NAFLD. This review aims to provide innovative therapeutic strategies for NAFLD.

The miR-23a ~ 27a ~ 24-2 cluster, commonly upregulated in diverse cancers, including hepatocellular carcinoma (HCC), raises questions about the specific functions of its three mature miRNAs and their integrated function. Utilizing CRISPR knockout (KO), CRISPR interference (CRISPRi), and CRISPR activation (CRISPRa) technologies, we established controlled endogenous miR-23a ~ 27 ~ a24-2 cell models to unravel their roles and signaling pathways in HCC. Both miR-23a KO and miR-27a KO displayed reduced cell growth in vitro and in vivo, revealing an integrated oncogenic function. Functional analysis indicated cell cycle arrest, particularly at the G2/M phase, through the downregulation of CDK1/cyclin B activation. High-throughput RNA-seq, combined with miRNA target prediction, unveiled the miR-23a/miR-27a-regulated gene network, validated through diverse technologies. While miR-23a and miR-27a exhibited opposing roles in cell migration and mesenchymal-epithelial transition, an integrated CRISPRi/a analysis suggested an oncogenic role of the miR-23a ~ 27a ~ 24-2 cluster in cell migration. This involvement potentially encompasses two signaling axes: miR-23a-BMPR2 and miR-27a-TMEM170B in HCC cells. In conclusion, our CRISPRi/a study provides a valuable tool for comprehending the integrated roles and underlying mechanisms of endogenous miRNA clusters, paving the way for promising directions in miRNA-targeted therapy interventions.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Surgery has been the major treatment method for HCC owing to HCC's poor sensitivity to radiotherapy and chemotherapy. However, its effectiveness is limited by postoperative tumour recurrence and metastasis. Systemic therapy is applied to eliminate postoperative residual tumour cells and improve the survival of patients with advanced HCC. Recently, the emergence of various novel targeted and immunotherapeutic drugs has significantly improved the prognosis of advanced HCC. However, targeted and immunological therapies may not always produce complete and long-lasting anti-tumour responses because of tumour heterogeneity and drug resistance. Traditional and patient-derived cell lines or animal models are used to investigate the drug resistance mechanisms of HCC and identify drugs that could reverse the resistance. This study comprehensively reviewed the established methods and applications of in-vivo and in-vitro HCC drug resistance models to further understand the resistance mechanisms in HCC treatment and provide a model basis for possible individualised therapy.

In recent years, the detection and analysis of circulating tumor DNA (ctDNA) have emerged as a new focus in the field of cancer research, particularly in the early diagnosis of hepatocellular carcinoma (HCC) and monitoring of therapeutic efficacy. ctDNA, which refers to cell-free DNA fragments released into the bloodstream from tumor cells upon cell death or shedding, carries tumor-specific genetic and epigenetic alterations, thereby providing a non-invasive approach for cancer diagnosis and prognosis. The concentration of ctDNA in the blood is higher compared to that in healthy individuals or other liquid biopsies from early-stage cancers, which is closely associated with the early diagnosis and comprehensive sequencing studies of HCC. Recent studies have indicated that sequential ctDNA analysis in patients receiving primary or adjuvant therapy for HCC can detect treatment resistance and recurrence before visible morphological changes in the tumor, making it a valuable basis for rapid adjustment of treatment strategies. However, this technology is continuously being optimized and improved. Challenges such as enhancing the accuracy of ctDNA sequencing tests, reducing the burden of high-throughput sequencing on a large number of samples, and controlling variables in the assessment of the relationship between ctDNA concentration and tumor burden, need to be addressed. Overall, despite the existing challenges, the examination and analysis of ctDNA have opened up new avenues for early diagnosis and therapeutic efficacy monitoring in hepatocellular carcinoma, expanding the horizons of this field.

Hepatocellular carcinoma (HCC) poses a significant threat to human health. Resistance to sorafenib in the chemotherapy of HCC is a common and significant issue that profoundly impacts clinical treatment. While several members of the transmembrane (TMEM) protein family have been implicated in the occurrence and progression of HCC, the association between TMEM39b and HCC remains unexplored. This study revealed a significant overexpression of TMEM39b in HCC, which correlated with a poor prognosis. Subsequent investigation revealed that RAS-selective lethal 3 (RSL3) induced pronounced ferroptosis in HCC, and knocking down the expression of TMEM39b significantly decreased its severity. Similarly, following the induction of ferroptosis in HCC by sorafenib, knocking down the expression of TMEM39b also decreased the severity of ferroptosis, enhancing HCC tolerance to sorafenib. In conclusion, we propose that TMEM39b promotes tumor progression and resistance to sorafenib by inhibiting ferroptosis in HCC.

Ferroptosis, an emerging type of programmed cell death, is initiated by iron-dependent and excessive ROS-mediated lipid peroxidation, which eventually leads to plasma membrane rupture and cell death. Many canonical signalling pathways and biological processes are involved in ferroptosis. Furthermore, cancer cells are more susceptible to ferroptosis due to the high load of ROS and unique metabolic characteristics, including iron requirements. Recent investigations have revealed that ferroptosis plays a crucial role in the progression of tumours, especially HCC. Specifically, the induction of ferroptosis can not only inhibit the growth of hepatoma cells, thereby reversing tumorigenesis, but also improves the efficacy of immunotherapy and enhances the antitumour immune response. Therefore, triggering ferroptosis has become a new therapeutic strategy for cancer therapy. In this review, we summarize the characteristics of ferroptosis based on its underlying mechanism and role in HCC and provide possible therapeutic applications.

Pulmonary fibrosis (PF) is a chronic interstitial lung disorder characterized by abnormal myofibroblast activation, accumulation of extracellular matrix (ECM), and thickening of fibrotic alveolar walls, resulting in deteriorated lung function. PF is initiated by dysregulated wound healing processes triggered by factors such as excessive inflammation, oxidative stress, and coronavirus disease (COVID-19). Despite advancements in understanding the disease's pathogenesis, effective preventive and therapeutic interventions are currently lacking. Ferroptosis, an iron-dependent regulated cell death (RCD) mechanism involving lipid peroxidation and glutathione (GSH) depletion, exhibits unique features distinct from other RCD forms (e.g., apoptosis, necrosis, and pyroptosis). Imbalance between reactive oxygen species (ROS) production and detoxification leads to ferroptosis, causing cellular dysfunction through lipid peroxidation, protein modifications, and DNA damage. Emerging evidence points to the crucial role of ferroptosis in PF progression, driving macrophage polarization, fibroblast proliferation, and ECM deposition, ultimately contributing to alveolar cell death and lung tissue scarring. This review provides a comprehensive overview of the latest findings on the involvement and signaling mechanisms of ferroptosis in PF pathogenesis, emphasizing potential novel anti-fibrotic therapeutic approaches targeting ferroptosis for PF management.

Hepatocellular carcinoma (HCC), one of the leading causes of cancer‑related mortality worldwide, is challenging to identify in its early stages and prone to metastasis, and the prognosis of patients with this disease is poor. Treatment options for HCC are limited, with even radical treatments being associated with a risk of recurrence or transformation in the short term. Furthermore, the multi‑tyrosine kinase inhibitors approved for first‑line therapy have marked drawbacks, including drug resistance and side effects. The rise and breakthrough of immune checkpoint inhibitors (ICIs) have provided a novel direction for HCC immunotherapy but these have the drawback of low response rates. Since avoiding apoptosis is a universal feature of cancer, the induction of non‑apoptotic regulatory cell death (NARCD) is a novel strategy for HCC immunotherapy. At present, NARCD pathways, including ferroptosis, pyroptosis and necroptosis, are novel potential forms of immunogenic cell death, which have synergistic effects with antitumor immunity, transforming immune 'cold' tumors into immune 'hot' tumors and exerting antitumor effects. Therefore, these pathways may be targeted as a novel treatment strategy for HCC. In the present review, the roles of ferroptosis, pyroptosis and necroptosis in antitumor immunity in HCC are discussed, and the relevant targets and signaling pathways, and the current status of combined therapy with ICIs are summarized. The prospects of targeting ferroptosis, pyroptosis and necroptosis in HCC immunotherapy are also considered.

Long-chain fatty acyl-Coa ligase 4 (ACSL4) is an important enzyme that converts fatty acids to fatty acyl-Coa esters, there is increasing evidence for its role in carcinogenesis. However, the precise role of ACLS4 in hepatocellular carcinoma (HCC) is not clearly understood. In the present study, we provide evidence that ACSL4 expression was specifically elevated in HCC and is associated with poor clinical outcomes. ACSL4 significantly promotes the growth and metastasis of HCC both in vitro and in vivo. RNA sequencing and functional experiments showed that the effect of ACSL4 on HCC development was heavily dependent on PAK2. ACSL4 expression is well correlated with PAK2 in HCC, and ACSL4 even transcriptionally increased PAK2 gene expression mediated by Sp1. In addition, emodin, a naturally occurring anthraquinone derivative, inhibited HCC cell growth and tumor progression by targeting ACSL4. In summary, ACSL4 plays a novel oncogene in HCC development by regulating PAK2 transcription. Targeting ACSL4 could be useful in drug development and therapy for HCC.