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Cancer stem cells (CSCs) play a substantial role in cancer onset and recurrence. Anomalous iron and lipid metabolism have been documented in CSCs, suggesting that ferroptosis, a recently discovered form of regulated cell death characterised by lipid peroxidation, could potentially exert a significant influence on CSCs. However, the precise role of ferroptosis in gastric cancer stem cells (GCSCs) remains unknown. To address this gap, we screened ferroptosis-related genes in GCSCs using The Cancer Genome Atlas and corroborated our findings through quantitative polymerase chain reaction and western blotting. These results indicate that stearoyl-CoA desaturase (SCD1) is a key player in the regulation of ferroptosis in GCSCs. This study provides evidence that SCD1 positively regulates the transcription of squalene epoxidase (SQLE) by eliminating transcriptional inhibition of P53. This mechanism increases the cholesterol content and the elevated cholesterol regulated by SCD1 inhibits ferroptosis via the mTOR signalling pathway. Furthermore, our in vivo studies showed that SCD1 knockdown or regulation of cholesterol intake affects the stemness of GCSCs and their sensitivity to ferroptosis inducers. Thus, targeting the SCD1/squalene epoxidase/cholesterol signalling axis in conjunction with ferroptosis inducers may represent a promising therapeutic approach for the treatment of gastric cancer based on GCSCs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Objectives: Acute kidney injury (AKI) caused by cisplatin (CDDP) is a complex, critical illness with no effective or specific treatment. The purpose of the study was to assess the protective effect of protopanaxadiol (PPD) on the kidneys in CDDP-induced AKI models and its possible mechanisms., Methods: In vitro, the protection of PPD was assessed in HK-2. KM mice were injected with CDDP to induce AKI models in vivo. The determination of blood urea nitrogen and serum creatinine (SCr) was performed, and pathological changes were examined by histopathological examination. Immunostaining and western blot analyses were used to analyze the expression levels of proteins., Results: PPD can increase the viability of HK-2 cells damaged by CDDP, improve cell morphology, and alleviate the symptoms of AKI in mice. In addition, PPD can down-regulate the protein expression of TRF and up-regulate the protein expression of Ferritin heavy chain, Glutathione peroxidase 4, and ferroptosis suppressor protein 1 reduce the iron content in cells and kidney tissues, and restore the antioxidant defense system., Conclusion: PPD has an inhibitory effect on cisplatin-induced nephrotoxicity, which may be related to the inhibition of ferroptosis by regulating iron metabolism and lipid peroxidation., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Gastric cancer (GC) is a serious disease with high morbidity and mortality rates worldwide. Chemotherapy plays a key role in GC treatment, while inevitable drug resistance and systematic side effects hinder its clinical application. Fenton chemistry-based chemodynamic therapy (CDT) has been used as a strategy for cancer ferroptosis, and the CDT efficiency could be enhanced by photothermal therapy (PTT). With the trend of treatment and diagnosis integration, the combination of magnetic resonance imaging (MRI) and CDT/PTT exhibits enormous progress. Herein, we constructed a platform based on PEGylated manganese-containing polydopamine (PDA) nanoparticles, named as PEG-PDA@Mn (PP@Mn) NPs. The PP@Mn NPs were stable and globular. Furthermore, they demonstrated near-infrared (NIR)-triggered PTT and Fenton-like reaction-based CDT effects and T1-weighted MRI capabilities. According to in vitro studies, the PP@Mn NPs trigger ferroptosis in cancer cells by producing abundant reactive oxygen species (ROS) via a Fenton-like reaction combined with PTT. Furthermore, in vivo studies showed that, under MRI guidance, the PP@Mn NPs combined with the PTT at the tumor region, have CDT anti-tumor effect. In conclusion, the PP@Mn NPs could provide an effective strategy for CDT/PTT synergistic ferroptosis therapy for GC.

[Display omitted] • Biomimetic CMnMPt exhibited homologous targeting function for gastric cancer. • Upon exposure to GSH, MnMPt was biodegraded, resulting in Mn2+ and Pt(II) release. • Pt(II) enhance Mn2+-mediated Fenton reaction, contributing to LPO generation. • The accumulation of LPO and consumption of GSH caused by CMnMPt, lead to ferroptosis. • CMnMPt activates anti-tumor immunity via triggering ferroptosis-mediated ICD effect. Selective induction of ferroptosis of cancer cells would be a promising approach to trigger immunogenic cell death (ICD) and sequentially potentiate immunotherapy. Actually, the efficiency to produce toxic lipid peroxides (LPO) and deplete glutathione (GSH) at the tumor site plays a key role in inducing ferroptosis. Herein, a cancer targeted cascade nanosystem (CCM@Mn@MSN-Pt(IV), CMnMPt) was constructed for synergistic chemo-dynamic and chemotherapy by conjugating Mn ions-doped mesoporous silica nanoparticles (Mn@MSN) and cisplatin prodrug (Pt(IV)), with cancer cell membrane cloaking. Owing to the bio-mimetic surface functionalization, the immune escape and homologous targeting behaviors of CMnMPt would dramatically enhance its cancer targeting and retention abilities. Once internalized by cancer cells, intracellular GSH would be depleted attributed to the bio-degradation of Mn@MSN and reduced of Pt(IV), resulting in Mn2+ release and cisplatin transform (from Pt(IV) to Pt(II)). Subsequently, generated Pt(II)) could damage nuclear DNA, and further activate nicotinamide adenine dinucleotide phosphate oxidases (NOXs) to enhance downstream H 2 O 2 levels. Additionally, Mn2+ ions could catalyze H 2 O 2 into highly reactive hydroxyl radical (OH), which results in a further increase in LPO content. In summary, CMnMPt could induce ferroptosis-mediated ICD, and recruit cytotoxic T lymphocytes cells, offering potential clinical applications to facilitate anti-tumor immunotherapy. [ABSTRACT FROM AUTHOR]