Schisandrin B exhibits anti-proliferative effects by inducing ferroptosis in pancreatic cancer
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens
SUBMITTER: 
Fengjin Li
PROVIDER: PXD078099 | iProX | Wed May 06 00:00:00 BST 2026
REPOSITORIES: iProX
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Project description:Pancreatic cancer (PC) is a lethal malignancy of the digestive system with an extremely low survival rate. Schisandrin B (Sch B) has demonstrated novel pre-clinical antitumor activity in several animal tumor models. However, it remains unclear whether Sch B exerts antitumor effects in PC. The molecular mechanisms underlying the antitumor properties of Sch B were explored using RNA sequencing.
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Project description:Mitochondria play a critical role in initiating and amplifying ferroptosis. VDAC1 embedded in the mitochondrial outer membrane, exerts a crucial role in regulation of ferroptosis. However, the mechanisms of VDAC1 oligomerization in regulating ferroptosis are not well elucidated. Here, we identified that VSTM2L, a novel VDAC1 binding protein, is positively associated with prostate cancer (PCa) progression, and a key regulator of ferroptosis. Moreover, VSTM2L knockdown in PCa cells enhanced the sensibility of RSL3-induced ferroptosis. Mechanistically, VSTM2L forms complex with VDAC1 and HK2, enhancing their binding affinity and preventing VDAC1 oligomerization, thereby inhibiting ferroptosis and maintaining mitochondria homeostasis in vitro and in vivo. Collectively, our findings reveal a pivotal role for VSTM2L in driving ferroptosis resistance and highlight its potential as a ferroptosis-inducing therapeutic target for the treatment of PCa.
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Project description:Nrf1 is a transcription factor that is highly conserved and reacts to oxidative, proteotoxic and endoplasmic reticulum stress in cells; nonetheless, its function in the context of acute kidney injury (AKI) remains unclear. Using a model of cisplatin-induced nephrotoxicity in vitro and in vivo, we found that the expression of Nrf1, which is expressed at high levels in renal tubular cells, was significantly downregulated after cisplatin treatment. Proximal tubule-specific Nrf1 knockout worsened and Nrf1 overexpression attenuated cisplatin-induced (CI)-AKI. RNA sequencing analysis revealed that Nrf1 overexpression decreased the number of transcripts involved in cell death, specifically those associated with ferroptosis, after cisplatin treatment. Furthermore, ferroptosis responses, characterized by increased lipid peroxidation and iron content and decreased FPN, XCT and glutathione peroxidase 4 levels, were attenuated in Nrf1-overexpressing HK-2 cells but worsened in Nrf1-knockout mice and Nrf1-knockdown HK-2 cells. Moreover, lipidomic and RNA sequencing results indicated that Nrf1 regulated the levels of polyunsaturated fatty acids (PUFAs) and inhibited the expression of ACSL4. Additionally, ChIP experiments revealed that Nrf1 bound to the promoter region of ACSL4, thereby inhibiting its transcription. Furthermore, inhibitors of ACSL4 significantly reduced the sensitivity of HK-2 cells to ferroptosis induced by Nrf1 knockdown. Collectively, these findings suggest that Nrf1 is a novel target for inhibiting ferroptosis in renal tubule cells by suppressing the transcription and expression of ACSL4, thereby reducing PUFA levels. Consequently, activators developed for Nrf1 may hold therapeutic potential in the treatment of patients with CI-AKI.
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Project description:This study aimed to investigate impact of myeloid ferritin heavy chain (FtH) deletion on iron trafficking in kidney health and disease. Myeloid FtH deletion (FtHΔ/Δ) led to upregulation of synuclein-α (Snca) as the only iron-binding protein. When exposed to kidney injury, FtHΔ/Δ mice exhibited significantly worse kidney function. Transcriptome analysis identified ferroptosis as a key pathway triggered by FtH deletion. This was confirmed by elevated expression of ferroptosis-related genes, oxidative stress markers, and increased iron deposition in the kidneys. The latter was mediated via reprogramming of macrophages to an iron-recycling phenotype by inducing Spic. Mechanistically, we demonstrate ferrireductase activity of monomeric Snca acts as a catalyst triggering oxidative stress and ferroptosis. Moreover, kidney accumulation of Snca is promoted in kidney diseases marked by heavy leukocyte infiltration in both mice and humans. These findings emphasize role of FtH in regulating iron metabolism and promoting kidney repair by suppressing Snca and Spic.
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Project description:Background: Characterized by high incidence, mutilation, and death rate, acute ischemic stroke (AIS) has threatened people’s health seriously. Therefore, there is an urge need for early diagnosis and effective treatment of AIS. The purpose of this study was to clarify the regulatory role and potential molecular mechanism of miR-342-5p and circRNA_0008146 in AIS. Materials and Methods: Small RNA sequencing analysis was performed to screen differentially expressed miRNAs between the AIS and control group. Middle cerebral artery occlusion/reperfusion (MCAO/R) models were constructed in C57BL/6J mice. The circRNA_0008146 and miRNA expression levels were detected by quantitative real-time PCR. Assay kits were used to determine Fe2+ levels and assess a battery of oxidative stress indicators, including ROS, MDA, LPO, SOD, and GSH/GSSG. The content of ACSL4 was measured by Western blot. The neurobehavioral manifestation was evaluated using the modified Neurological Severity (mNSS) Score, rotarod test, and corner test. TTC staining was employed to detect cerebral infarction volume. Nissl staining was adapted to detect histological change and neuronal damage. Results: RNA sequencing analysis revealed miR-342-5p was significantly downregulated in the plasma of AIS patients. MiR-342-5p inhibited oxidative stress and RSL3-induced ferroptosis after cerebral ischemic-reperfusion injury in vivo by targeting ferroptosis-related gene ACSL4. CircRNA_0008146 acted as a sponge of miR-342-5p, and overexpression of circRNA_0008146 increased brain damage in stroke mice. CircRNA_0008146 contributed to ferroptosis in cerebral infraction via sponging miR-342-5p to regulate ACSL4. Conclusion: CircRNA_0008146/miR-342-5p/ACSL4 axis regulate ferroptosis after cerebral ischemia-reperfusion, which may be a potential therapeutic target for ischemic stroke.
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Project description:Liver fibrosis (LF) is a pathological condition that if not controlled can progress into liver sclerosis and malignant tumors. Ferroptosis has been comprehensively studied and found to improve LF by exacerbating hepatic cell ferroptosis. Ginsenoside RK1 (GRK1) is an essential component of ginseng with anti-fibrotic effects. However, the anti-LF mechanism of GRK1 remains elusive. The impact of GRK1 on LF was evaluated via RNA-sequence analysis of GRK1-treated hepatic stellate cells (HSC). Furthermore, cellular thermal shift assay, drug affinity responsive target stability, and molecular docking analyses were carried out to verify the interaction between GRK1 and HK2. The fibrosis indicators and histopathology assessment revealed that GRK1 substantially suppressed CCl4-induced LF in mice. Moreover, GRK1 markedly improved MDA, lipid ROS, and liver Fe2+ in CCl4-stimulated mice. This study revealed that GRK1 targets HK2 in HSC-T6 cells to stimulate the ACSL4/LPCAT3/ALOX5 pathway, thereby inducing HSC ferroptosis and alleviating hepatic fibrosis.
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