Background: As a pivotal point for the development of liver diseases, liver fibrosis (LF) is closely associated with cellular senescence and ferroptosis. However, there is a lack of effective markers that accurately predict LF status. This study aims to identify key genes involved in LF through bioinformatics analysis and experimental validation. Methods: We used bioinformatics analysis of Gene Expression Omnibus (GEO) data to investigate the gene functions, prognostic value, and immune associations of characteristic genes in LF. Functional enrichment analysis of DEGs was performed using GO and KEGG. Immune cell types and their proportions were estimated with CIBERSORTx. In addition, we analyzed the role of NQO1 in LF using IHC, WB, PCR, and flow cytometry. Results: Bioinformatics analysis identified 10 hub genes, including AR, CDKN1A, GJA1, CTSB, HIF1A, HMGB1, NQO1, PARP1, PTEN, and TXN. Among them, NQO1 was strongly correlated with immune cell activity. Experimental validation confirmed that NQO1 is upregulated and promotes αSMA and COL1A1 expression in hepatic stellate cells (HSCs). Knockdown of NQO1 significantly affected the proliferation of HSCs. Conclusions: NQO1 plays a critical role in HSC senescence and ferroptosis, promoting HSC activation and contributing to LF progression. Our findings suggest that NQO1 may serve as a potential biomarker for LF.

Microplastics (MPs), as the crucial environmental pollutants, can be easily transported into the human body and accumulate in the liver. However, current studies mainly focus on acute exposure to MPs, investigations on long-term interactions with MPs alone remain limited. Thereby, we examined noxious properties of MPs and selected the most common polystyrene (PS) MPs as the research object, including unmodified PS MPs (PS-MPs) and positive-charged PS MPs (PS-NH2) at 10 mg/L employing oral drinking water methods in mice for six consecutive months in vivo. In vitro, we treated the human hepatocyte cells with MPs at 25 μg/mL to explore involved mechanisms. The results revealed that six-month MPs exposure led to nonalcoholic fatty liver disease (NAFLD) including impaired liver functions, extensive lipid depositions accompanied by abnormal levels of metabolic genes and PS-NH2 MPs exerted a stronger effect than PS-MPs. Concurrently, mice treated with MPs revealed the accumulation of senescent hepatocytes, leading to increased secretions of senescent phenotypes in the liver. We also discovered that MPs initiated the HO-1/Nrf2 axis consequently inducing ferroptosis in vivo and in vitro, as shown by massive iron deposition, extensive lipid peroxidation along with significant protein expressions in ferroptosis-related markers. Additionally, targeting the HO-1/Nrf2 pathway to further alleviate ferroptosis with corresponding inhibitors could efficiently alleviate cell senescence. Therefore, our study reveals new evidence of the relationship between chronic exposure to MPs and NAFLD and furthers the understanding of how plastic pollution affects human health.

In this editorial, we comment on the article by Zhou et al published in a recent issue. We specifically focus on the crucial roles of ferroptosis and pyroptosis in acute liver failure (ALF), a disease with high mortality rates. Ferroptosis is the result of increased intracellular reactive oxygen species due to iron accumulation, glutathione (GSH) depletion, and decreased GSH peroxidase 4 activity, while pyroptosis is a procedural cell death mediated by gasdermin D which initiates a sustained inflammatory process. In this review, we describe the characteristics of ferroptosis and pyroptosis, and discuss the involvement of the two cell death modes in the onset and development of ALF. Furthermore, we summarize several interfering methods from the perspective of ferroptosis and pyroptosis for the alleviation of ALF. These observations might provide new targets and a theoretical basis for the treatment of ALF, which are also crucial for improving the prognosis of patients with ALF.

In this editorial, we comment on the article published in the recent issue of the World Journal of Gastroenterology. Acute liver failure (ALF) is a fatal disease that causes uncontrolled massive hepatocyte death and rapid loss of liver function. Ferroptosis and pyroptosis, cell death forms that can be initiated or blocked concurrently, can play significant roles in developing inflammation and various malignancies. However, their roles in ALF remain unclear. The article discovered the positive feedback between ferroptosis and pyroptosis in the progression of ALF, and revealed that the silent information regulator sirtuin 1 (SIRT1) inhibits both pathways through p53, dramatically reducing inflammation and protecting hepatocytes. This suggests the potential use of SIRT1 and its downstream molecules as therapeutics for ALF. Thus, we will discuss the role of ferroptosis and pyroptosis in ALF and the crosstalk between these cell death mechanisms. Additionally, we address potential treatments that could alleviate ALF by simultaneously inhibiting both cell death pathways, as well as examples of SIRT1 activators being used as disease treatment strategies, providing new insights into the therapy of ALF.

Ferroptosis, a newly proposed concept of programmed cell death, has garnered significant attention in research across different diseases in the last decade. Despite thorough citation analyses in neuroscience, there is a scarcity of information on ferroptosis research specifically related to neurodegenerative diseases.

The Web of Science Core Collection database retrieved relevant articles and reviews. Data on publications, countries, institutions, authors, journals, citations, and keywords in the included studies were systematically analyzed using Microsoft Excel 2019 and CiteSpace 6.2.R7 software.

A comprehensive analysis and visualization of 563 research papers on ferroptosis in neurodegenerative diseases from 2014 to 2023 revealed emerging research hotspots and trends. The number of annual publications in this field of study has displayed a pattern of stabilization in the early years of the decade, followed by a notable increase in the later years and peaking in 2023 with 196 publications. Regarding publication volume and total citations, notable research contributions were observed from countries, institutions, and authors in North America, Western Europe, and China. Current research endeavors primarily focus on understanding the intervention mechanisms of neurodegenerative diseases through the ferroptosis pathway and exploring and identifying potential therapeutic targets.

The study highlights key areas of interest and emerging trends in ferroptosis research on neurodegenerative diseases, offering valuable insights for further exploration and potential directions for diagnosing and treating such conditions.

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.