UNC-51-like kinase 1 (ULK1), a primary serine/threonine kinase, is implicated in diverse pathophysiological processes. Previous findings have linked ULK1-dependent autophagy to cardiac hypertrophy. Our study further explored the functional role and molecular mechanisms of ULK1 in non-autophagic signaling pathways. Notably, ULK1 expression was significantly elevated in both transverse aortic constriction (TAC)-induced hypertrophic mouse hearts and Angiotensin II (Ang II)-treated cardiomyocytes, suggesting an increased sensitivity to hypertrophic stimuli potentially mediated by ULK1-induced ferroptosis in hypertrophic cardiomyocytes. Treatment with the ferroptosis inhibitor ferrostatin-1 (Fer-1) effectively reduced ULK1-induced cardiomyocyte hypertrophy and ferroptosis. Proteomic analysis identified the upregulation of transcription factor high mobility group A2 (HMGA2) as a key mechanism in this ferroptotic process. Elevated HMGA2 levels exacerbated ferroptosis, evidenced by increased cell death, lipid peroxidation, ROS production, and reduced GPX4 expression. Furthermore, HMGA2 was shown to promote cardiomyocyte ferroptosis via binding to methyltransferase-like 14 (METTL14), which in turn enhanced ferroptosis in cardiomyocytes through solute carrier family 7 member 11 (SLC7A11) m6A modification. In vivo, a delivery system using neutrophil membrane (NM)-coated mesoporous silica nanoparticles (MSN) was developed to inhibit cardiac hypertrophy, underscoring the therapeutic potential of targeting ULK1. Overall, this study demonstrates that ULK1 promotes cardiac hypertrophy through HMGA2/METTL14/SLC7A11 axis-mediated cardiomyocyte ferroptosis, suggesting a novel therapeutic approach for cardiac hypertrophy.

In recent years, the incidence and mortality rates of pancreatic cancer have been rising, posing a severe threat to human health. Tumor heterogeneity remains a critical barrier to advancing diagnosis and treatment efforts. The lack of specific early symptoms, limited early diagnostic methods, high biological complexity, and restricted therapeutic options contribute to the poor outcomes and prognosis of pancreatic cancer. Therefore, there is an urgent need to explore the different subtypes in-depth and develop personalized therapeutic strategies tailored to each subtype. Increasing evidence highlights the pivotal role of molecular subtyping in treating pancreatic cancer. This review focuses on recent advancements in classifying molecular subtypes and therapeutic approaches, discussed from the perspectives of gene mutations, genomics, transcriptomics, proteomics, metabolomics, and immunomics.

Glutathione peroxidase 4 (GPX4) is a crucial antioxidant enzyme that plays a vital role in protecting cells from oxidative damage and lipid peroxidation. In the context of skin diseases, GPX4 serves as a key regulator of oxidative stress and inflammation, both of which are significant features of various skin conditions. By preventing lipid peroxidation and maintaining membrane integrity, GPX4 acts as a safeguard against cell death pathways, particularly ferroptosis, in skin diseases. Dysregulation of GPX4 in conditions such as dermatitis, psoriasis, and skin cancer is linked to heightened oxidative stress, inflammation, and tissue damage. Understanding the role of GPX4 and its intricate interactions in skin disease pathogenesis can aid in more effectively targeting oxidative stress and inflammation, leading to promising therapeutic interventions. This review summarizes the role of GPX4 in maintaining skin homeostasis and its involvement in disease, proposing strategies to target GPX4, including its post-translational modifications. Investigate the precise mechanism through which GPX4 influences the onset of skin diseases, and utilize GPX4 agonists or inhibitors as potential treatments.

The autoimmune disorder known as Systemic Lupus Erythematosus (SLE) exhibits intricate features with abnormal immune responses leading to tissue injury. The generation of antibodies and the disruption of immune regulation heavily depend on the pivotal function of T follicular helper (Tfh) cells. Iron dysregulation is significant in autoimmune diseases, impacting immune cell function and disease progression. Our study investigates the role of the HMGA1/EZH2/STAT3/GPX4 axis in modulating Tfh cells and iron homeostasis in SLE. Abnormal Tfh cell populations in SLE patients demonstrate reduced susceptibility to iron-induced cell death, with HMGA1 identified as a key player in Tfh cell proliferation and sensitivity to iron-induced death. Experimental interventions reveal the inhibitory role of the HMGA1 axis in Tfh cells' susceptibility to iron-induced death, suggesting therapeutic avenues for SLE and related autoimmune disorders. Our study underscores the importance of iron homeostasis in autoimmune conditions, providing novel insights and treatment strategies for further research in this field.

Prostate cancer (PCa) remains a significant global health burden and an increase in oxidative stress is associated with cancer progression. High Mobility Group A2 (HMGA2), a chromatin architectural protein, increases oxidative stress and promotes sensitivity to ferroptosis inducers, however, the mechanism is unknown. We investigated the role of HMGA2 in GPX4 regulation and the impact on cellular responses to oxidative stress and ferroptosis sensitivity. We conducted UALCAN database analysis, western blot analysis, and lipid peroxidation assays to determine the relationship between HMGA2 and GPX4 and the levels of lipid reactive oxygen species in a panel of PCa cell lines, including an enzalutamide-resistant cancer cell line (C4-2B MDVR). Our results show an inverse relationship between HMGA2 and GPX4 expression with high HMGA2 and low GPX4 expression associated with higher Gleason score and lower survival probability in prostate adenocarcinoma (PRAD) patients, while low/moderate HMGA2 expression is positively associated with increased GPX4 expression and higher survival probability. Cell lines showed a moderately negative but not statistically significant correlation between HMGA2 and GPX4 expression, however, PC3 and DU145 PCa cells display higher lipid peroxides concomitant with higher endogenous levels of HMGA2 and low GPX4. Overexpression of wild-type HMGA2 in LNCaP and 22Rv1 cells leads to higher HMGA2 expression compared to Neo control and is associated with higher SLC7A11 and GPX4 expression, while interestingly truncated HMGA2 overexpression in LNCaP and 22Rv1 cells coincides with higher HMGA2 and reduced GPX4 expression, leading to increased lipid peroxides and susceptibility to ferroptosis. Overexpression of wild-type and truncated HMGA2 in 22Rv1 cells increases SLC7A11 mRNA yet differing GPX4 protein expression suggests posttranslational regulation of GPX4. Moreover, enzalutamide-resistant C4-2B MDVR cells display higher HMGA2 levels compared to C4-2B cells, as well as sensitivity to RSL3 ferroptosis inducer, which is partially reversed by ferroptosis inhibitor, ferrostatin-1. Interestingly, GPX4 expression is higher in C4-2B MDVR cells compared to C4-2B, and HMGA2 knockdown further increases its expression but does not significantly alter its susceptibility to ferroptosis. In conclusion, our study shows that HMGA2 regulation of GPX4 expression is complex and truncated HMGA2 downregulates GPX4 and increases lipid peroxides. Moreover, HMGA2-expressing cells including enzalutamide-resistant cells are susceptible to RSL-3-induced ferroptosis. Thus, ferroptosis sensitivity offers promising insights for the development of targeted therapeutic interventions for aggressive PCa.

Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a critical pathway in cancer biology. This review delves into the epigenetic mechanisms that modulate ferroptosis in cancer cells, focusing on how DNA methylation, histone modifications, and non-coding RNAs influence the expression and function of essential genes involved in this process. By unraveling the complex interplay between these epigenetic mechanisms and ferroptosis, the article sheds light on novel gene targets and functional insights that could pave the way for innovative cancer treatments to enhance therapeutic efficacy and overcome resistance in cancer therapy.

Gastric cancer (GC) is a common malignant tumor, long non-coding RNA and microRNA (miRNA) are important regulators that affect tumor proliferation, metastasis and chemotherapy resistance, and thus participate in tumor progression. CASC19 is a new bio-marker which can promote tumor invasion and metastasis. However, the mechanism by which CASC19 affects the progression of GC through miRNA is not clear.

To explore the role of the CASC19/miR-491-5p/HMGA2 regulatory axis in GC.

To explore the expression and prognosis of CASC19 in GC through clinical samples, and investigate the effects of inhibiting CASC19 on the proliferation, migration, invasion and other functions of GC cells through cell counting Kit-8 (CCK-8), ethynyldeoxyuridine, Wound healing assay, Transwell, Western blot and flow cytometry experiments. The effect of miR-491-5p and HMGA2 in GC were also proved. The regulatory relationship between CASC19 and miR-491-5p, miR-491-5p and HMGA2 were validated through Dual-luciferase reporter gene assay and reverse transcription PCR. Then CCK-8, Transwell, Wound healing assay, flow cytometry and animal experiments verify the role of CASC19/miR-491-5p/HMGA2 regulatory axis.

The expression level of CASC19 is related to the T stage, N stage, and tumor size of patients. Knockdown of the expression of CASC19 can inhibit the ability of proliferation, migration, invasion and EMT conversion of GC cells, and knocking down the expression of CASC19 can promote the apoptosis of GC cells. Increasing the expression of miR-491-5p can inhibit the proliferation of GC cells, miR-491-5p mimics can inhibit EMT conversion, and promote the apoptosis of GC cells, while decreasing the expression of miR-491-5p can promote the proliferation and EMT conversion and inhibit the apoptosis of GC cells. The expression of HMGA2 in GC tissues is higher than that in adjacent tissues. At the same time, the expression level of HMGA2 is related to the N and T stages of the patients. Reducing the level of HMGA2 can promote cell apoptosis and inhibit the proliferation of GC cells. Cell experiments and animal experiments have proved that CASC19 can regulates the expression of HMGA2 through miR-491-5p, thereby affecting the biological functions of GC.

CASC19 regulates the expression of HMGA2 through miR-491-5p to affect the development of GC. This axis may serve as a potential biomarker and therapeutic target of GC.

Inhibition of activated hepatic stellate cells (HSCs) is a promising approach for treating liver fibrosis, and the ferroptosis has emerged as a pivotal mechanism to achieve this inhibition. The effects of naringenin, a flavonoid with anti-inflammatory properties, have not been thoroughly examined in liver fibrosis. Therefore, we used cholestasis model to study the effect of naringenin on liver fibrosis. Our findings demonstrated a significant exacerbation of liver tissue damage and fibrosis in mice subjected to bile duct ligation (BDL), accompanied by a substantial upregulation of fibrogenesis-related gene expression. Notably, naringenin administration markedly alleviated liver injury and fibrosis in these mice. Furthermore, naringenin exhibited inhibitory effects on the activation of HSCs, concurrently inducing ferroptosis. Importantly, naringenin significantly increased autophagic activity in HSCs. This effect was counteracted by co-administration of the autophagy inhibitor 3-MA, leading to a notable reduction in naringenin-induced HSC ferroptosis. In BDL model mice, naringenin demonstrated a mitigating effect on liver fibrosis, suggesting a potential correlation with naringenin-induced ferroptosis of HSCs. These results provide novel insights into the molecular mechanisms of naringenin-induced ferroptosis and highlight autophagy-dependent ferroptosis as a promising therapeutic strategy for liver fibrosis.