Ferroptosis in colonic epithelial cells has been implicated in the development of ulcerative colitis (UC) and the accompanying gut leakage. Scutellaria baicalensis Georgi (Scu) is widely used herb medicine for alleviating UC.

We aimed to clarify the therapeutic effect of Scu on UC by inhibiting intestinal epithelial cell ferroptosis and explore its regulatory mechanisms on lipid peroxidation and the GPX4/ACSL4 pathways.

UPLC-Q-TOF/MS was employed to analyze chemicals in the herbal extract and the colonic exposure of prototypes in Scu-treated mice. Additionally, the main compounds were quantified using HPLC-UV. The ameliorative effects of Scu were comprehensively explored in a UC mouse model established by feeding with dextran sulfate sodium (DSS). HPLC-MS based metabolomic studies were conducted to identify the differential metabolites in colon tissues from Scu or vehicle treated UC mice. Network pharmacology was conducted for target prediction and potential pathway analysis. In conjunction with these bioinformatic analyses, we performed RT-qPCR, immunofluorescence, immunohistochemistry and immunoblotting to elucidate the regulatory mechanisms of Scu on ferroptosis-related pathways in both in vivo and in vitro models.

78 chemical constituents in Scu were characterized, with 42 detected in the colonic tissues of Scu-treated mice. Scu could alleviate UC related symptoms in mice, including increased colon length and decreased pathological score. Furthermore, Scu inhibited pro-inflammatory cytokines and mediators, while improving gut barrier function by increasing the expression of ZO-1 and Occludin at both mRNA and protein levels. Based on metabolomic studies, a total of 71 differential metabolites exhibited a reversal trend following Scu administration. These findings, combined with results from network pharmacology, suggest that arachidonic acid (AA) metabolism and ferroptosis may serve as potential pathways for Scu intervention in UC. Further experiments indicated that the amelioratory actions of Scu on ferroptosis partially contributed to its modulation on lipid peroxidation and its regulatory influence on the GPX4/ASCL4 axis to ameliorate UC. When AA was administered at the same time as concurrently with Scu, the regulatory effects of Scu on ferroptosis, GPX4/ASCL4 axis, and its protective effects against UC were significantly reduced. Moreover, the inhibitory effect of Scu on ferroptosis was weakened when we knocked down GPX4 or overexpressed ACSL4 in vitro.

The ameliorative effect of Scu in UC is closely related to the regulation of lipid peroxidation and GPX4/ASCL4 mediated intestinal epithelial ferroptosis.

Ferroptosis is an emerging form of programmed cell death triggered by iron-dependent lipid peroxidation. It is distinguished from other forms of cell death by its unique morphological changes and characteristic fine-tuned regulatory gene network. Since its pivotal involvement in the pathogenesis and therapeutic interventions of various diseases, such as malignant tumors, cardiovascular and cerebrovascular diseases, and traumatic disorders, has been well-established, ferroptosis has garnered significant attention in contemporary physiological and pathological research. For the advantage of alleviating the clinical symptoms and improving life quality, traditional Chinese medicine (TCM) holds a significant position in the treatment of these ailments. Moreover, increasing studies revealed that TCM compounds and monomers showed evident therapeutic efficacy by regulating ferroptosis via signaling pathways that tightly regulate redox reactions, iron ion homeostasis, lipid peroxidation, and glutathione metabolism. In this paper, we summarized the current knowledge of TCM compounds and monomers in regulating ferroptosis, aiming to provide a comprehensive review of disease management by TCM decoction, Chinese patent medicine, and natural products deriving from TCM through ferroptosis modulation. The formulation composition, chemical structure, and possible targets or mechanisms presented here offer valuable insights into the advancement of TCM exploration.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease, characterized by focal iron overload. Herein, we reported that γ-glutamylcysteine (γGC) deletion in UC lesions intensified the disease by depleting intracellular GSH to induce macrophage ferroptosis, leading to macrophage M1 reprogramming and eventually exacerbating inflammation. To counteract this, the advanced microparticles (MPs)-based delivery system is selected to encapsulate γGC. The resulting γGC-MPs displayed the same porous and spiky morphology as their substrate's natural pollens, resulting in improved intestinal adhesion and enhanced lesion contact of γGC-MPs. Our results demonstrated that exogenous γGC supplementation could inhibit macrophage M1 polarization by restraining ferroptosis, as well as suppressing the PI3K/AKT pathway and TNF signaling pathway. Compared with free γGC, γGC-MPs significantly alleviated typical UC symptoms in dextran sulfate sodium (DSS)-induced colitis, evidenced by reduced intestinal inflammation, restored intestinal barrier function, and improved microbiota composition. Consequently, this study addressed critical gaps in understanding the causes of ferroptosis and its impact on macrophage reprogramming in UC, offering a novel synergistic therapeutic strategy for UC.

Sepsis is a disease with high mortality caused by a dysregulated response to infection. Ferroptosis is a newly discovered type of cell death. Ferroptosis-related genes are involved in the occurrence and development of sepsis. However, research on the diagnostic value of ferroptosis-related protein biomarkers in sepsis serum is limited. This study aims to explore the clinical value of Ferroptosis-related proteins in diagnosing sepsis and predicting mortality risk.

A single-center, prospective, observational study was conducted from January to December 2023, involving 170 sepsis patients, 49 non-septic ICU patients, and 50 healthy individuals. Upon ICU admission, biochemical parameters, GCS, SOFA, and APACHE II scores were recorded, and surplus serum was stored at -80°C for biomarker analysis via ELISA. Diagnostic efficacy was evaluated using ROC curve analysis.

Baseline serum levels of ACSL4, GPX4, PTGS2, CL-11, IL-6, IL-8, PCT, and hs-CRP significantly differed among sepsis, non-septic, and healthy individuals (all p-value < 0.01). ACSL4, GPX4, PTGS2, IL-6, IL-8, PCT, and hs-CRP demonstrated high diagnostic and differential diagnostic performance (AUC: 0.6688 to 0.9945). IL-10 and TNF-α showed good diagnostic performance (AUC = 0.8955 and 0.7657, respectively). ACSL4 (AUC = 0.7127) was associated with predicting sepsis mortality. Serum levels of ACSL4, CL-11, and IL-6 above the cut-off value were associated with shorter survival times. ACSL4 levels were positively correlated with SOFA (Rho = 0.354, p-value < 0.0001), APACHE II (Rho = 0.317, p-value < 0.0001), and septic shock (Rho = 0.274, p-value = 0.003) scores but negatively correlated with the GCS score (Rho = -0.218, p-value = 0.018). GPX4 levels were positively correlated with SOFA (Rho = 0.204, p-value = 0.027) and APACHE II (Rho = 0.233, p-value = 0.011) scores.

ACSL4 and GPX4 have strong diagnostic and differential diagnostic value in sepsis, including the ability to predict 28-day mortality in sepsis patients, and may become new potential serum markers for the diagnostic and differential diagnostic of sepsis.

Inflammatory bowel disease (IBD) includes chronic inflammatory conditions, such as Crohn's disease and ulcerative colitis, characterized by impaired function of the intestinal mucosal epithelial barrier. In recent years, ferroptosis, a novel form of cell death, has been confirmed to be involved in the pathological process of IBD and is related to various pathological changes, such as oxidative stress and inflammation. Recent studies have further revealed the complex interactions between the microbiome and ferroptosis, indicating that ferroptosis is an important target for the regulation of IBD by the gut microbiota and its metabolites. This article reviews the significant roles of gut microbial metabolites, such as short-chain fatty acids, tryptophan, and bile acids, in ferroptosis in IBD. These metabolites participate in the regulation of ferroptosis by influencing the intestinal microenvironment, modulating immune responses, and altering oxidative stress levels, thereby exerting an impact on the pathological development of IBD. Treatments based on the gut microbiota for IBD are gradually becoming a research hotspot. Finally, we discuss the potential of current therapeutic approaches, including antibiotics, probiotics, prebiotics, and fecal microbiota transplantation, in modulating the gut microbiota, affecting ferroptosis, and improving IBD symptoms. With a deeper understanding of the interaction mechanisms between the gut microbiota and ferroptosis, it is expected that more precise and effective treatment strategies for IBD will be developed in the future.

Intervertebral disc degeneration (IVDD) is a natural process that occurs with aging and is the main cause of low back pain. Basic helix-loop-helix ARNT-like 1 (BMAL1) plays key roles in the pathogenesis of many diseases. The present study investigates the role of curculigoside (CUR), which has been reported to be a potential anti-apoptotic compound in other diseases.

Dysregulated genes were identified by RNA sequencing (RNA-seq). Western blotting (WB), immunohistochemistry, immunofluorescence (IF) staining, and real-time fluorescent quantitative polymerase chain reaction were used to detect BMAL1 expression in 25 human intervertebral disc specimens (male: female =13:12), tissues from BMAL1-knockout mice and from an IVDD mouse model. The regulatory effects of CUR and BMAL1 in nucleus pulposus (NP) cells after Small Interfering RNA (siRNA) transfection were examined by flow cytometry, IF staining and WB. The therapeutic effect of intraperitoneal CUR injection was also evaluated in mice.

BMAL1 expression was negatively correlated with IVDD severity and was significantly lower in degenerative NP cells. After BMAL1 knockdown using siRNA, the apoptosis rate of degenerative NP cells was significantly higher, while transfection with a lentivirus overexpressing BMAL1 exerted the opposite effect. Bioinformatics analysis revealed that BMAL1 is regulated by the JAK-STAT3 pathway, and CUR upregulated BMAL1 expression by inhibiting STAT3 phosphorylation, subsequently alleviating NP cell apoptosis and increasing extracellular matrix (ECM) components., thus alleviating IVDD.

CUR can inhibit apoptosis and improve the ECM by upregulating BMAL1 expression, which is reduced in IVDD. This study provides a therapeutic strategy to alleviate apoptosis associated with inflammation-induced IVDD.

We investigated ferroptosis, a type of programmed cell death mechanism, in human hearts donated after brain death (DBD) and those donated after circulatory death (DCD), focusing on warm ischemia time (WIT) and cold storage. A total of 24 hearts were procured, with six from the DBD group and 18 from the DCD group. The DCD group was divided into three subgroups, each containing six hearts, based on different WITs of 20, 40, and 60 min. All procured hearts were placed in cold storage for up to 6 h. Left ventricular biopsies were performed at 0, 2, 4, and 6 h. We measured ferroptosis regulators [glutathione peroxidase 4 (GPX4), acyl-CoA synthetase long chain family member 4 (ACSL4), and transferrin receptor], iron content (Fe2+ and Fe3+), and lipid peroxidation (malondialdehyde, MDA) in the cardiac tissue. Modulation of ferroptosis was observed in both DBD and DCD hearts. Warm ischemia injury increased myocardial vulnerability to ferroptotic cell death. For DBD hearts, up to 6 h of cold storage increases cardiac levels of MDA, iron content, and ACSL4, thereby increasing vulnerability to ferroptotic cell death. In contrast, for DCD hearts with a WIT of 40 min or more, warm ischemia injury was identified as the primary factor contributing to increased myocardial susceptibility to ferroptotic cell death. Ferroptosis may serve as a promising target to optimize cold preservation for DBD hearts. For DCD hearts, strategies to inhibit ferroptosis should focus on the early warm ischemia phase to assess donor heart quality and suitability for transplantation.NEW & NOTEWORTHY The first human heart research explored the effects of ischemia on the myocardial ferroptotic cell death mechanism. Prolonged cold storage increases the susceptibility of DBD hearts to ferroptotic cell death. In contrast, warm ischemic injury appears to be the main factor leading to the vulnerability of DCD heart ferroptosis. Targeting ferroptosis could be beneficial in optimizing cold preservation for DBD hearts. However, for DCD hearts, interventions should focus on the early phase of warm ischemia.

Patients with osteosarcoma (OS) exhibit metastasis upon diagnosis, and the condition frequently acquires resistance to traditional chemotherapy treatments, failing the therapy. The objective of this research was to examine the impact of curculigoside (Cur), a key phenolic compound discovered in the rhizome of C. orchioides Gaertn, on OS cells and the surrounding tumor environment.

We assessed the impact of curculigoside on tumor inhibition in four osteosarcoma cell lines and mice tumor xenograft models using various techniques including cell viability assay, wound healing assay, cell apoptosis analysis, immunofluorescent staining, and IHC. Moreover, we created a mini-PDX model by utilizing freshly obtained primary OS cells from surgically removed OS tissues to evaluate the possible clinical use of Cur.

The results of our study show that Cur triggers cell death in OS cells and enhances the maturation of RAW264.7 cells. By effectively inhibiting the growth of OS cells, these actions mechanistically trigger the catastrophic buildup of unbound iron and uncontrolled lipid peroxidation, ultimately resulting in ferroptosis. Moreover, additional validation of Cur's substantial antineoplastic impact is obtained through in vivo experiments employing xenograft and mini-PDX models.

To sum up, this research is the initial one to exhibit the anti-tumor effects of Cur on OS using various methods, indicating that Cur shows potential as a viable approach for treating OS.

Inflammatory bowel disease (IBD) is an autoimmune disorder primarily characterized by intestinal inflammation and recurrent ulceration, leading to a compromised intestinal barrier and inflammatory infiltration. This disorder's pathogenesis is mainly attributed to extensive damage or death of intestinal epithelial cells, along with abnormal activation or impaired death regulation of immune cells and the release of various inflammatory factors, which contribute to the inflammatory environment in the intestines. Thus, maintaining intestinal homeostasis hinges on balancing the survival and functionality of various cell types. Programmed cell death (PCD) pathways, including apoptosis, pyroptosis, autophagy, ferroptosis, necroptosis, and neutrophil extracellular traps, are integral in the pathogenesis of IBD by mediating the death of intestinal epithelial and immune cells. Natural products derived from plants, fruits, and vegetables have shown potential in regulating PCD, offering preventive and therapeutic avenues for IBD. This article reviews the role of natural products in IBD treatment by focusing on targeting PCD pathways, opening new avenues for clinical IBD management.

The incidence of ulcerative colitis (UC) has been rising rapidly in recent years, and there is currently no effective method to prevent its recurrence. Owing to its long treatment duration, difficulty in treatment, prolonged remission, and high costs, it has attracted global attention. Exploring safe, effective, and sustainable treatment regimens has become an urgent global issue. Traditional Chinese medicine (TCM) has unique advantages such as low cost, low drug resistance, and fewer side effects, and has accumulated rich experience in the treatment of UC.

Ferroptosis, as a new form of non-apoptotic cell death, is characterized by iron homeostatic imbalance and lipid peroxidation in the redox system. Studies have shown that inhibited ferroptosis in intestinal epithelial cells can protect the intestinal mucosa. Targeted intervention in ferroptosis may be a new direction for the treatment of UC.

We conducted a systematic literature search with Google Scholar, PubMed, Web of Science, ScienceDirect and X-mol databases have been utilized to retrieve relevant literature up to October 2024, using keywords included ferroptosis, Inflammatory bowel disease (IBD), UC, Crohn's disease and TCM, Chinese traditional prescription, Chinese medicine extract and active ingredients. The existing literature was comprehensively studied and sorted out.

Currently, UC is mainly treated with drugs, including corticosteroids, amino salicylates, biologics, and immunomodulators, but drug resistance and adverse reactions are common. Increasing evidence suggests that TCM may treat UC by interfering with ferroptosis. Scholars have confirmed that TCM can inhibit ferroptosis, and recent studies have shown that TCM can not only inhibit iron dependent lipid peroxidation in intestinal cells but also enhance the antioxidant and anti-inflammatory abilities of intestinal mucosa, thus playing a role in the treatment of UC. This review explores the relevance of TCM intervention in ferroptosis and the treatment of UC, discusses the possible mechanisms of ferroptosis in UC, and aims to provide a basis for the diagnosis and treatment of UC.

It is revealed that TCM targeted ferroptosis has a good application prospect in the treatment of UC, providing a theoretical basis for elucidating the pathogenesis of UC and the study of TCM targeting ferroptosis regulating lipid metabolism in the treatment of UC, and providing a new perspective for the treatment of IBD in the future.

Spinal cord injury (SCI) is a severe neurological disorder that can lead to paralysis or death. Oxidative stress during SCI is a critical phase causing extensive nerve cell damage and apoptosis, thereby impairing spinal cord healing. Thus, a primary goal of SCI drug therapy is to mitigate oxidative stress. Curculigoside (CUR), a phenolic glucoside extracted from the dried root and rhizome of Curculigo orchioides Gaertn, possesses neuroprotective and antioxidant properties. This study aimed to investigate whether CUR effectively promotes the recovery of spinal cord tissue following SCI and elucidate its mechanism. We employed a hydrogen peroxide (H2O2)-induced PC12 cell model and an SCI rat model to observe the effects of CUR on oxidation and apoptosis. The results demonstrated that CUR significantly reduced the expression of apoptosis-related proteins (Bax and Caspase-3), Annexin V/propidium iodide (PI), and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), while increasing the expression of the anti-apoptotic protein Bcl-2. Moreover, CUR effectively enhanced levels of antioxidants (glutathione [GSH)] and decreased reactive oxygen species (ROS) in vitro. Furthermore, CUR facilitated functional recovery through its anti-apoptotic and anti-oxidative stress effects on spinal cord tissues in SCI rats. These effects were mediated via the Nrf2/NQO1 signaling pathway. Therefore, our study showed that CUR acted as an anti-apoptotic and anti-oxidative stress agent, inhibiting astrocyte activation and promoting neuronal reconstruction and functional recovery. These findings may contribute significantly to the development of SCI treatments and advance the field of SCI drug therapy.

Ulcerative colitis (UC) is a chronic form of inflammatory bowel disease, which current treatments often show limited effectiveness. Ferroptosis, a newly recognized form of programmed cell death has been implicated in UC pathogenesis, suggesting that it may be viable therapeutic target. Tetrastigma hemsleyanum (TH) has shown potential anti-UC effects, though it is unclear whether its therapeutic benefits are mediated by ferroptosis.

This study investigated the involvement of ferroptosis in the therapeutic effects of TH and identified key active components and pathways of TH against UC.

The ethyl acetate extract of TH (TH_E) was found to be the most effective anti-inflammatory extract compared with the petroleum ether extract (TH_P), n-butanol extract (TH_N), and water-soluble extract (TH_W). TH_E's components were identified using UHPLC-MS/MS, ADME parameters, and network pharmacology. Additionally, TH_E's effects on ferroptosis were evaluated in an LPS-induced RAW264.7 cell model.

TH_E exhibited the strongest anti-inflammatory activity among four extracts. 10 compounds (Linolenic acid; Apigenin; Protocatechualdehyde; Asiatic acid; Quercetin; Isorhamnetin; Kaempferol; Azelaic acid; Oleic Acid; Palmitic acid) were selected from SwissADME database. Then a total of 281 targets for these 10 compounds and 1330 UC-related targets were identified from different database. Isorhamnetin was selected as the most promising anti-inflammatory component among 10 components. Furthermore, enrichment analysis revealed that ferroptosis was involved in UC development, with both TH_E and isorhamnetin exhibited inhibition of ferroptosis. Finally, isorhamnetin's anti-ferroptosis effects were linked to the Keap1/Nrf2/HO-1 pathway.

The results demonstrate that TH_E and isorhamnetin alleviate LPS-induced UC through restraining ferroptosis. Moreover, isorhamnetin's anti-UC properties are mediated by inhibiting ferroptosis via activation of the Keap1/Nrf2/HO-1 axis.

Changyanning tablets (CYN) are a marketed traditional Chinese medicine composed of Diijincao (Euphorbia humifusa Willd.), Jinmaoercao (Hedyotis chrysotricha (Palib.) Merr.), Zhangshugen (root of Cinnamomum camphora (L.) J.Presl), Xiangru (Elsholtzia ciliate (Thunb.) Hyl.), and Fengxiangshuye (leaf of Liquidambar formosana Hance). They possess the functions of clearing heat, removing dampness, and regulating qi. CYN is used for the treatment of diarrhea and dysentery caused by damp heat in the large intestine, with symptoms such as diarrhea, or stools with pus and blood, tenesmus, abdominal pain and distension, acute and chronic gastroenteritis, diarrhea, bacterial diarrhea, and indigestion in children.

This study aims to explore the intervention effects of CYN on Crohn's disease (CD) and its potential mechanisms.

The therapeutic effect and potential mechanism of CYN on CD were investigated based on the 2,4,6-Trinitrobenzenesulfonic acid solution (TNBS)-induced rat model. In vivo and in vitro experiments confirmed that CYN can alleviate CD by inhibiting GPX4-mediated ferroptosis. siRNA was used to knock down GPX4 for reverse validation. Finally, active components of CYN inhibiting ferroptosis were identified using UPLC-MS and the RSL3-induced HCoEpiC ferroptosis cell model.

CYN significantly improved ferroptosis-related indicators (GSH, MDA, GPX4, and SLC7A11) in the colons of TNBS-induced CD rats. Screening with three ferroptosis inducers (RSL3, FINO2, and erastin) revealed that CYN was most effective against RSL3 (a ferroptosis inducer targeting GPX4)-induced apoptosis. Subsequently, the resistance effect of CYN on RSL3-induced ferroptosis was confirmed in vitro. Further in vivo experiments showed that CYN alleviated local CD-like intestinal injury induced by RSL3 enema. siRNA knockdown of GPX4 in HCoEpiC cells further validated GPX4 as major target of CYN in inhibiting ferroptosis. Finally, UPLC-MS and in vitro experiments identified rutin, rosmarinic acid, and kaempferol-3-O-sophoroside as key active components of CYN for inhibiting ferroptosis.

CYN alleviates CD by inhibiting GPX4-mediated ferroptosis, highlighting its clinical potential for treating CD and enhancing the understanding of the pathogenic and therapeutic mechanisms associated with CD.

Taohong Siwu Decoction (TSD) is a well-known traditional Chinese medicine (TCM) prescription. It consists of six crude herbs, including Rehmannia glutinosa Libosch, Paeonia lactiflora Pall, Angelica sinensis (Oliv.) Diels, Ligusticum chuanxiong Hort., Prunus persica (L.) Batsch, Cauthamus tinctorius L. It has been used to treat blood stasis syndrome in Chinese clinics for thousands of years. According to recent research, TSD may be useful in the management of abnormal uterine bleeding (AUB). The aim of the present study is to investigate the possible mechanism of TSD on AUB after drug-induced incomplete abortion.

To investigate whether TSD could be effective in ameliorating AUB through inhibiting acyl-CoA synthetase long-chain family member 4 (ACSL4)-mediated ferroptosis.

An incomplete medical aborting model was established and Ishikawa cell lines were utilized in vitro. The quantity of uterine bleeding was measured by alkaline hemoglobin photometry. Pathological results were observed by hematoxylin-eosin staining (HE). Mitochondrial morphology and function were measured by transmission electron microscopy. The related protein and mRNA were detected by western blot, the real-time reverse transcriptase-polymerase chain reaction (RT-qPCR). We used knockdown and overexpression of ACSL4 to investigate the influence of ferroptosis in Ishikawa cells and the impact of TSD on ferroptosis.

TSD dramatically reduced the amount and duration of bleeding as well as the endometrial inflammation of AUB. TSD improved mitochondrial characteristics, decreased ACSL4 protein and mRNA levels. The ferroptosis marker glutathione (GSH) levels were increased, on the contrary, reactive oxygen species (ROS) and iron levels decreased when TSD intervened. TSD decreased levels of the inflammatory factors and the oxidative products.

TSD alleviated endometrial inflammation by inhibiting ACSL4-mediated ferroptosis and exerts a protective effect of AUB.

The lack of knowledge about the mechanism of hyperoxia-induced intestinal injury has attracted considerable attention, due to the potential for this condition to cause neonatal complications. This study aimed to explore the relationship between hyperoxia-induced oxidative damage and ferroptosis in intestinal tissue and investigate the mechanism by which hyperoxia regulates inflammation through ferroptosis. The study systematically evaluated the effects of hyperoxia on oxidative stress, mitochondrial damage, ferroptosis, and inflammation of intestinal epithelial cells both in vitro and in vivo. The results showed that ferroptosis was involved in intestinal oxidative damage caused by hyperoxia and was regulated by Nrf2. Moreover, hyperoxia-induced oxidative damage regulated inflammation through ferroptosis by upregulating the COX-2/PGE2/EP2 signaling pathway. These findings have important implications for future clinical prevention and therapeutic approaches to neonatal organ injury caused by hyperoxia treatment.

Recent findings underscore the significance of ferroptosis, an innovative iron-dependent mode of cell death, in the etiology and progression of chronic kidney disease (CKD). Nucleophosmin 1 (NPM1), a nucleolar protein, contributes to fibrogenesis and modulates cellular functions and mortality. Initial investigations utilized bioinformatics techniques to pinpoint genes with altered expression in CKD and to forecast the potential links between NPM1, ferroptosis, and renal fibrosis. Increased NPM1 expression was verified in the renal tissues of CKD patients. Experimental models of renal fibrosis in both animals and cells were then used for further study. The suppression of NPM1 led to an augmentation in iron metabolism and lipid peroxidation processes integral to ferroptosis, contributing to the mitigation of renal fibrosis. In contrast, an elevation in NPM1 expression had the opposite effect. This modulation may be interconnected with the nuclear factor erythroid 2-related factor 2 pathway. Moreover, the application of the ferroptosis inhibitor, Fer-1, not only obstructed ferroptosis but also diminished NPM1 expression, which, in turn, contributed to the alleviation of renal fibrosis. Thus, our findings suggest that in CKD the NPM1 level increased and led to decreased ferroptosis and aggravated renal fibrosis via an Nrf2 pathway. Ferroptosis inhibitor can alleviate renal fibrosis.

The pathophysiology of cardiovascular disease (CVD) is complex and presents a serious threat to human health. Cardiomyocyte loss serves a pivotal role in both the onset and progression of CVD. Among various forms of programmed cell death, ferroptosis, along with apoptosis, autophagy and pyroptosis, is closely linked to the advancement of CVD. Ferroptosis, a mechanism of cell death, is driven by the buildup of oxidized lipids and excess iron. This pathway is modulated by lipid, amino acid and iron metabolism. Key characteristics of ferroptosis include disrupted iron homeostasis, increased peroxidation of polyunsaturated fatty acids due to reactive oxygen species, decreased glutathione levels and inactivation of glutathione peroxidase 4. Treatments targeting ferroptosis could potentially prevent or alleviate CVD by inhibiting the ferroptosis pathway. Ferroptosis is integral to the pathogenesis of several types of CVD and inhibiting its occurrence in cardiomyocytes could be a promising therapeutic strategy for the future treatment of CVD. The present review provided an in‑depth analysis of advancements in understanding the mechanisms underlying ferroptosis. The present manuscript summarized the interplay between ferroptosis and CVDs, highlighting its dual roles in these conditions. Additionally, potential therapeutic targets within the ferroptosis pathway were discussed, alongside the current limitations and future directions of these novel treatment strategies. The present review may offer novel insights into preventive and therapeutic approaches for CVDs.

UC, also known as ulcerative colitis, is an inflammatory bowel disease that is chronic and nonspecific. Palmatine (PAL), a natural alkaloid active ingredient, has demonstrated predominant protective effects on UC. In spite of this, PAL on UC is unclear in terms of its underlying mechanisms. Thus, this study aimed to investigate its effects and mechanism. By inducing rats with 5 % dextran sulfate sodium (DSS), an in vivo model of UC was developed. and then oral PAL administration. In vitro viability of NCM460 cells was measured using Cell Counting Kit-8. An enzyme-linked immunosorbent assay was used to determine the levels of inflammatory factores. The levels of oxidative stress parameters were also assessed, and the expression level of cyclooxygenase-2 (COX-2), acyl-CoA synthetase long-chain family member 4 (ACSL4), glutathione peroxidase 4 (GPX4), NF-E2-related factor 2(Nrf2), phospho-Nrf2, and heme oxygenase-1 (HO-1) was detected by Western blot. An iron kit was employed to measure iron content in cells and colonic tissues. Results indicated that PAL treatment significantly improved UC in rats, as shown by reduced disease activity index scores and increased colon length, which decreased IL-18, IL-1β, IL-6, TNF-α, MDA, NO, and LDH levels, but increased GSH level in DSS-induced rats and NCM460 cells. Further, PAL treatment markedly decreased COX-2, ACSL4, Nrf2, and HO-1 expression levels while increasing that of GPX4 and phospho-Nrf2. Furthermore, PAL inhibited the iron overload in the cells and colonic tissues. PAL may protect against UC by inhibiting the inflammatory response, oxidative stress, iron load, and suppressing ferroptosis pathway.

Iron overload disrupts gut microbiota and induces ferroptosis, contributing to colitis. However, whether gut microbiota directly drives iron overload-induced colitis and its underlying mechanism remain unclear.

The study aimed to explore whether gut microbiota can directly regulate iron overload-induced colitis and its underling mechanism.

Male C57BL/6N mice were fed with ferrous sulfate to establish an iron overload model. Antibiotics and dextran sulfate sodium salt (DSS) were used to create germ-free and colitis models, respectively.

Results showed that iron overload caused disruption of systemic iron homeostasis via activating pro-inflammation response, which caused induction of ferroptosis and eventually resulted in colitis in mice. Notably, iron overload inhibited System Xc- and activated the nuclear factor E2-related factor 2/heme oxygenase-1 pathway, driving ferroptosis and colitis progression. Similar results were observed in mouse colon epithelial cells, which were treated with high doses ferric ammonium citrate. Additionally, iron overload exacerbated DSS-induced colitis by activating the ferroptosis and increasing harmful bacteria (e.g., Mucispirillum) abundance. Interestingly, eliminating gut microbiota attenuated iron overload-induced colitis, without affecting systemic inflammation through inhibiting ferroptosis of mice. Depletion of the gut microbiota partially mitigated the exacerbating effect of iron overload on DSS-induced colitis through inhibiting ferroptosis of mice.

Iron overload activates ferroptosis in colonic cells, increases the relative abundance of harmful bacteria, and exacerbates DSS-induced colitis in mice. Iron overload exacerbates DSS-induced ferroptosis and colitis in a microbiota-dependent manner. Targeting gut microbiota may offer new strategies for managing iron overload-induced colitis.

Ferroptosis is a novel form of programmed cell death characterized by iron accumulation, lipid peroxidation, and a decline in antioxidant capacity, all of which are regulated by gene expression. The onset of numerous diseases is closely associated with ferroptosis. Common diseases affect a large population, reduce the quality of life, and impose an increased burden on the healthcare system. The role of ferroptosis in common diseases, its therapeutic potential, and even its translation into clinical drug treatments are currently significant research topics worldwide. This study preliminarily explores the theoretical basis of ferroptosis, its mechanism and treatment prospect in common diseases including ischaemia-reperfusion injury, inflammatory bowel diseases, liver fibrosis, acute kidney injury, diabetic kidney disease, stroke, Alzheimer's disease, cardiovascular disease, immune and cancer. This review provides a theoretical foundation for the further study and development of ferroptosis, as well as for the prevention and treatment of common diseases.

Ferroptosis is a nonapoptotic form of cell death characterized by iron-dependent lipid peroxidation in membrane phospholipids. Since its identification in 2012, extensive research has unveiled its involvement in the pathophysiology of numerous diseases, including cancers, neurodegenerative disorders, organ injuries, infectious diseases, autoimmune conditions, metabolic disorders, and skin diseases. Oxidizable lipids, overload iron, and compromised antioxidant systems are known as critical prerequisites for driving overwhelming lipid peroxidation, ultimately leading to plasma membrane rupture and ferroptotic cell death. However, the precise regulatory networks governing ferroptosis and ferroptosis-targeted therapy in these diseases remain largely undefined, hindering the development of pharmacological agonists and antagonists. In this review, we first elucidate core mechanisms of ferroptosis and summarize its epigenetic modifications (e.g., histone modifications, DNA methylation, noncoding RNAs, and N6-methyladenosine modification) and nonepigenetic modifications (e.g., genetic mutations, transcriptional regulation, and posttranslational modifications). We then discuss the association between ferroptosis and disease pathogenesis and explore therapeutic approaches for targeting ferroptosis. We also introduce potential clinical monitoring strategies for ferroptosis. Finally, we put forward several unresolved issues in which progress is needed to better understand ferroptosis. We hope this review will offer promise for the clinical application of ferroptosis-targeted therapies in the context of human health and disease.

Ferroptosis is a type of regulated cell death that occurs due to the iron-dependent accumulation of lethal reactive oxygen species (ROS) from lipids. Ferroptosis is characterized by distinct morphological, biochemical, and genetic features that differentiate it from other regulated cell death (RCD) types, which include apoptosis, various necrosis types, and autophagy. Recent reports show that ferritin formation is correlated to many disorders, such as acute injury, infarction, inflammation, and cancer. Iron uptake disorders have also been associated with intestinal epithelial dysfunction, particularly inflammatory bowel disease (IBD). Studies of iron uptake disorders may provide new insights into the pathogenesis of IBD, thereby improving the efficacy of medical interventions. This review presents an overview of ferroptosis, elucidating its fundamental mechanisms and highlighting its significant involvement in IBD.

Sophora flavescens is often used in traditional Chinese medicine for skin issues, diarrhea, and vaginal itching (Plant names have been checked with http://www.the/plant/list.org on Feb 22nd, 2024). Oxymatrine (OY), a major bioactive compound from Sophora flavescens, is commonly used in China to treat ulcerative colitis, but its mechanisms are still unclear.

Recent studies have found that the crosstalk between ferroptosis and inflammation is an important mechanism in the pathogenesis of UC. The aim of this study was to investigate the potential underlying mechanisms of OY treatment on DSS-induced ulcerative colitis, specifically focusing on the processes of ferroptosis and inflammation.

Bioinformatics methods were used to identify key targets of OY for ferroptosis and inflammation in ulcerative colitis, based on GEO data and FerrDb database. Then, 4% DSS solution was used to induce UC model. OY's impact on morphological changes was assessed using colon views, Hematoxylin and eosin (HE) staining, and transmission electron microscopy (TEM). Ferroptosis phenotype index and inflammations factors were detected by ELISA or chem-bio detection kits. The screen out hub related genes about ferroptosis and inflammation were verified by RT-PCR, immunohistochemistry (IHC), and western blotting (WB) respectively.

Bioinformatics results show that there are 16 key target genes involved in ferroptosis and inflammation interaction of OY treatment for UC, such as IL6, NOS2, IDO1, SOCS1, and DUOX. The results of animal experiments show that OY could depress inflammatory factors (IL-1β, IL-6, TNF-α, HMGB1, and NLRP3) and reduce iron deposition (Fe2+, GSH). Additionally, OY suppressed the hub genes or proteins expression involved in ferroptosis and inflammation, including IL-1β, IL-6, NOS2, HIF1A, IDO1, TIMP1, and DUOX2.

This present study combines bioinformatics, molecular biology, and animal experimental research evidently demonstrated that OY attenuates UC by improving ferroptosis and inflammation, mainly target to the expression of IL-1β, IL-6, NOS2, HIF1A, IDO1, TIMP1, and DUOX2.

Inflammatory diseases, including psoriasis, atherosclerosis, rheumatoid arthritis, and ulcerative colitis, are characterized by persistent inflammation. Moreover, the existing treatments for inflammatory diseases only provide temporary relief by controlling symptoms, and treatments of unstable and expensive. Therefore, new therapeutic solutions are urgently needed to address the underlying causes or symptoms of inflammatory diseases. Inflammation frequently coincides with a high level of (reactive oxygen species) ROS activation, serving as a fundamental element in numerous physiological and pathological phenotypes that can result in serious harm to the organism. Given its pivotal role in inflammation, oxidative stress, and ferroptosis, ROS represents a focal node for investigating the (nuclear factor E2-related factor 2) Nrf2 pathway and ferroptosis, both of which are intricately linked to ROS. Ferroptosis is mainly triggered by oxidative stress and involves iron-dependent lipid peroxidation. The transcription factor Nrf2 targets several genes within the ferroptosis pathway. Recent studies have shown that Nrf2 plays a significant role in three key ferroptosis-related routes, including the synthesis and metabolism of glutathione/glutathione peroxidase 4, iron metabolism, and lipid processes. As a result, ferroptosis-related treatments for inflammatory diseases have attracted much attention. Moreover, drugs targeting Nrf2 can be used to manage inflammatory conditions. This review aimed to assess ferroptosis regulation mechanism and the role of Nrf2 in ferroptosis inhibition. Therefore, this review article may provide the basis for more research regarding the treatment of inflammatory diseases through Nrf2-inhibited ferroptosis.

Inflammatory bowel disease (IBD) is a non-specific chronic inflammatory disorder of the gastrointestinal tract, imposing significant burdens on both society and individuals. As a new type of regulated cell death (RCD), ferroptosis is different from classic RCDs such as apoptosis and necrosis in cell morphology, biochemistry and genetics. The main molecular mechanisms of ferroptosis include dysregulation of iron metabolism, impaired antioxidant capacity, mitochondrial dysfunction, accumulation of lipid-associated super-oxides, and membrane disruption. In recent years, increasing evidence has shown that ferroptosis is involved in the pathophysiology of inflammatory bowel disease. However, the exact roles and underlying molecular mechanisms have not been fully elucidated. This article reviews the mechanism of ferroptosis in the occurrence and development of inflammatory bowel disease, in order to provide new ideas for the pathophysiological research of inflammatory bowel disease. Additionally, we discuss potential strategies for the prevention and treatment of inflammatory bowel disease by targeting ferroptosis.

The interplay between intestinal barrier degradation and trace element insufficiency worsens inflammatory bowel disease (IBD). Selenium (se) is essential for glutathione peroxidase 4 (GPX4) synthesis, which protects against intestinal epithelial cell injury in IBD. However, malnutrition and malabsorption limit the availability of dietary selenium. This study investigated the protective effects of naturally occurring seleno-amino acids on the intestinal barrier in an IBD animal model by promoting GPX4 synthesis. L-se-methylselenocystine (seMc) supplementation reversed decreased GPX4 expression levels, alleviated glutathione depletion and scavenged reactive oxygen species in vitro. In vivo, enteral nutrition combined with seMc protected the intestinal barrier and alleviated IBD-related symptoms by inhibiting ferroptosis and reversing lipid peroxidation in epithelial cells while reducing immune cell infiltration. Our findings suggest that seleno-amino acid-based nutritional formulations may provide a basis for nutritional support to alleviate complex cycles between intestinal barrier damage and malnutrition in IBD patients.

Group 3 innate lymphoid cells (ILC3s) are essential for both pathogen defense and tissue homeostasis in the intestine. Dysfunction of ILC3s could lead to increased susceptibility to intestinal inflammation. However, the precise mechanisms governing the maintenance of intestinal ILC3s are yet to be fully elucidated. Here, we demonstrated that ferroptosis is vital for regulating the survival of intestinal ILC3. Ferroptosis-related genes, including GPX4, a key regulator of ferroptosis, were found to be upregulated in intestinal mucosal ILC3s from ulcerative colitis patients. Deletion of GPX4 resulted in a decrease in NKp46+ILC3 cell numbers, impaired production of IL-22 and IL-17A, and exacerbated intestinal inflammation in a T cell-independent manner. Our mechanistic studies revealed that GPX4-mediated ferroptosis in NKp46+ILC3 cells was regulated by the LCN2-p38-ATF4-xCT signaling pathway. Mice lacking LCN2 in ILC3s or administration of a p38 pathway inhibitor exhibited similar phenotypes of ILC3 and colitis to those observed in GPX4 conditional knock-out mice. These observations provide novel insights into therapeutic strategies for intestinal inflammation by modulating ILC3 ferroptosis.

Worldwide, ulcerative colitis (UC) is becoming increasingly fast growing. Ginsenoside Rh2 has been reported to alleviate UC. However, the latent biological mechanism of Rh2 in the treatment of UC remains uncertain. In this study, the goal was to determine the therapeutic effect of Rh2 on dextran sulfate sodium (DSS)-induced UC.

A DSS-induced UC mouse model was established and divided into 7 groups for Rh2 gavage and/or miR-125a-5p lentivirus injection (n = 10 per group). Colonic specimens were collected for phenotypic and pathological analysis. miR-125a-5p and specific protein 1 (SP1) expression, inflammation-related factors IL-6 and IL-10, and apoptosis were detected in mice. Human normal colon epithelial cell line NCM460 was treated with H2O2 and ferric chloride hexahydrate to construct an in vitro cell model of colitis and induce ferroptosis. Independent sample t-test was used to compare cell proliferation, cell entry, apoptosis, and oxidative stress between the two groups. One way analysis of variance combined with the least significant difference t test was used for comparison between groups. Multiple time points were compared by repeated measurement analysis of variance.

DSS-induced UC mice had significantly decreased body weight, increased disease activity index, decreased colon length, and decreased miR-125a-5p expression (all P < 0.05). In the DSS-induced mouse model, the expression of miR-125a-5p rebounded and ferroptosis was inhibited after Rh2 treatment (all P < 0.05). Inhibition of miR-125a-5p or upregulation of SP1 expression counteracted the protective effects of Rh2 on UC mice and ferroptosis cell models (all P < 0.05).

Rh2 mitigated DSS-induced colitis in mice and restrained ferroptosis by targeting miR-125a-5p. Downregulating miR-125a-5p or elevating SP1 could counteract the protective impacts of Rh2 on ferroptotic cells. The findings convey that Rh2 has a latent application value in the treatment of UC.

Ferroptosis is a novel type of regulated cell death (RCD) involving iron accumulation and lipid peroxidation. Since its discovery in 2012, various studies have shown that ferroptosis is associated with the pathogenesis of various diseases. Ferroptotic cell death has also been linked to intestinal dysfunction but can act as either a positive or negative regulator of intestinal disease, depending on the cell type and disease context. The continued investigation of mechanisms underlying ferroptosis provides a wealth of potential for developing novel treatments. Considering the growing prevalence of intestinal diseases, particularly colorectal cancer (CRC) and inflammatory bowel disease (IBD), this review article focuses on potential therapeutics targeting the ferroptotic pathway in relation to CRC and IBD.

The notable decline in the number of Tregs within Necrotizing enterocolitis (NEC) intestinal tissues，contribute to excessive inflammation and necrosis, yet the precise underlying factors remain enigmatic. Ferroptosis, a novel cell death stemming from a disrupted lipid redox metabolism, is the focus of this investigation. Specifically, this study delves into the ferroptosis of Treg cells in the context of NEC and observes the protective effects exerted by vitamin E intervention, which aims to mitigate ferroptosis of Treg cells.

To investigate the reduction of Treg cells in NEC intestine, we analyzed its association with ferroptosis from multiple angles. We constructed a mouse with a specific knockout of Gpx4 in Treg cells, aiming to examine the impact of Treg cell ferroptosis on NEC intestinal injury and localized inflammation. Ultimately, we employed vitamin E treatment to mitigate ferroptosis in NEC intestine's Treg cells, monitoring the subsequent amelioration in intestinal inflammatory damage.

The diminution of Treg cells in NEC is attributed to ferroptosis stemming from diminished GPX4 expression. Gpx4-deficient Treg cells exhibit impaired immunosuppressive function and are susceptible to ferroptosis. This ferroptosis of Treg cells exacerbates intestinal damage and inflammatory response in NEC. Notably, Vitamin E can inhibit the ferroptosis of Treg cells, subsequently alleviating intestinal damage and inflammation in NEC. Additionally, Vitamin E bolsters the anti-lipid peroxidation capability of Treg cells by upregulating the expression of GPX4.

In the context of NEC, the ferroptosis of Treg cells represents a significant factor contributing to intestinal tissue damage and an exaggerated inflammatory response. GPX4 is pivotal for the viability and functionality of Treg cells. Vitamin E exhibits the capability to mitigate the ferroptosis of Treg cells, thereby enhancing their number and function, which plays a crucial role in mitigating intestinal tissue damage and inflammatory response in NEC.

Ferroptosis is a pervasive non-apoptotic form of cell death highly relevant in various degenerative diseases and malignancies. The hallmark of ferroptosis is uncontrolled and overwhelming peroxidation of polyunsaturated fatty acids contained in membrane phospholipids, which eventually leads to rupture of the plasma membrane. Ferroptosis is unique in that it is essentially a spontaneous, uncatalyzed chemical process based on perturbed iron and redox homeostasis contributing to the cell death process, but that it is nonetheless modulated by many metabolic nodes that impinge on the cells' susceptibility to ferroptosis. Among the various nodes affecting ferroptosis sensitivity, several have emerged as promising candidates for pharmacological intervention, rendering ferroptosis-related proteins attractive targets for the treatment of numerous currently incurable diseases. Herein, the current members of a Germany-wide research consortium focusing on ferroptosis research, as well as key external experts in ferroptosis who have made seminal contributions to this rapidly growing and exciting field of research, have gathered to provide a comprehensive, state-of-the-art review on ferroptosis. Specific topics include: basic mechanisms, in vivo relevance, specialized methodologies, chemical and pharmacological tools, and the potential contribution of ferroptosis to disease etiopathology and progression. We hope that this article will not only provide established scientists and newcomers to the field with an overview of the multiple facets of ferroptosis, but also encourage additional efforts to characterize further molecular pathways modulating ferroptosis, with the ultimate goal to develop novel pharmacotherapies to tackle the various diseases associated with - or caused by - ferroptosis.

The incidence and prevalence of inflammatory-related diseases (IRDs) are increasing worldwide. Current approved treatments for IRDs in the clinic are combat against inhibiting the pro-inflammatory cytokines. Though significant development in the treatment in the IRDs has been achieved, the severe side effects and inefficiency of currently practicing treatments are endless challenge. Drug discovery from natural sources is efficacious over a resurgence and also natural products are leading than the synthetic molecules in both clinical trials and market. The use of natural products against IRDs is a conventional therapeutic approach since it is a reservoir of unique structural chemistry, accessibility and bioactivities with reduced side effects and low toxicity. In this review, we discuss the cause of IRDs, treatment of options for IRDs and the impact and adverse effects of currently practicing clinical drugs. As well, the significant role of natural products against various IRDs, the limitations in the clinical development of natural products and thus pave the way for development of natural products as immunomodulators against IRDs are also discussed.

Ulcerative colitis (UC) is a form of chronic inflammatory bowel disease, and UC diagnosis rates continue to rise throughout the globe. The research and development of new drugs for the treatment of UC are urgent, and natural compounds are an important source. However, there is a lack of systematic summarization of natural compounds and their mechanisms for the treatment of UC.

We reviewed the literature in the databases below from their inception until July 2023: Web of Science, PubMed, China National Knowledge Infrastructure, and Wanfang Data, to obtain information on the relationship between natural compounds and UC.

The results showed that 279 natural compounds treat UC through four main mechanisms, including regulating gut microbiota and metabolites (Mechanism I), protecting the intestinal mucosal barrier (Mechanism II), regulating intestinal mucosal immune response (Mechanism III), as well as regulating other mechanisms (Mechanism Ⅳ) such as cellular autophagy modulation and ferroptosis inhibition. Of these, Mechanism III is regulated by all natural compounds. The 279 natural compounds, including 62 terpenoids, 57 alkaloids, 52 flavonoids, 26 phenols, 19 phenylpropanoids, 9 steroids, 9 saponins, 8 quinonoids, 6 vitamins, and 31 others, can effectively ameliorate UC. Of these, terpenoids, alkaloids, and flavonoids have the greatest potential for treating UC. It is noteworthy to highlight that a total of 54 natural compounds exhibit their therapeutic effects by modulating Mechanisms I, II, and III.

This review serves as a comprehensive resource for the pharmaceutical industry, researchers, and clinicians seeking novel therapeutic approaches to combat UC. Harnessing the therapeutic potential of these natural compounds may significantly contribute to the improvement of the quality of life of patients with UC and promotion of disease-modifying therapies in the future.