ROS Lipid Research Articles

GATA1 Transcriptionally Upregulates LMCD1, Promoting Ferroptosis in Sepsis-Associated Acute Kidney Injury Through the Hippo/YAP Pathway.

Sepsis-associated acute kidney injury (SA-AKI) is associated with morbidity and mortality. Ferroptosis is associated with the pathophysiology of SA-AKI. Here, we investigated the role of LIM and cysteine-rich domain 1 (LMCD1) in the regulation of ferroptosis during SA-AKI progression. SA-AKI models were established by CLP and LPS treatments. Hematoxylin and eosin (HE) and (PAS) staining were conducted to examine renal pathological changes. ELISA was used to measure serum creatinine and BUN levels. Lipid ROS levels in cells were examined using flow cytometry. MDA, GSH, SOD, and Fe2+ levels in the cells were measured using appropriate kits. Molecular interactions were analyzed using ChIP, a dual-luciferase reporter gene, and Co-IP assays. GATA1 knockdown inhibits LPS-induced cell injury, oxidative stress, and ferroptosis in HK-2 cells by transcriptionally inhibiting LMCD1 expression. Moreover, LMCD1 activates the Hippo/YAP pathway by promoting CUL3-mediated Nrf2 ubiquitination degradation. LMCD1 knockdown alleviates CLP-induced AKI in mice by inhibiting ferroptosis. Taken together, LMCD1 transcriptionally activated by GATA1 promotes ferroptosis during SA-AKI progression by activating the Hippo/YAP pathway and facilitating CUL3-mediated Nrf2 ubiquitination degradation.

Homocysteine induces ferroptosis in renal tubular epithelial cells via β-catenin/GPX4 signaling pathway

Hyperhomocysteinemia can cause severe damage to kidney. Ferroptosis represents a critical mechanism in the initiation and development of kidney disorders. We focus on the β-catenin/GPX4 signaling pathway to explore how homocysteine influences ferroptosis regulation in renal tubular epithelial cells. C57BL/6J mice were administered drinking water with high level of homocysteine to establish a hyperhomocysteinemia model. In the cell experiments, HKC-8 cells were exposed to homocysteine for a duration of 12 h. Active β-catenin, β-catenin, GPX4, FTH1, and KIM-1 were detected using Western blotting; Biochemical assays were conducted to measure lipid ROS, Fe2+, and GSH; GPX4 and β-catenin were detected through immunohistochemistry and immunofluorescence techniques; Mitochondrial damage was examined using transmission electron microscopy; ChIP analysis, coupled with dual-luciferase reporter gene assays, was employed to investigate the relationship between β-catenin protein and GPX4 gene promoter. Our findings revealed that homocysteine disrupted β-catenin signaling, inhibited GPX4 expression in renal tubular epithelial cells, subsequently promoted ferroptosis. Overexpression of β-catenin or GPX4 inhibited ferroptosis induced by homocysteine, and β-catenin regulated GPX4 expression in renal tubular epithelial cells. Further assays demonstrated that GPX4 acted as a target gene of β-catenin. In conclusion, homocysteine elicits ferroptosis in renal tubular epithelial cells by disrupting β-catenin signaling and inhibiting its target gene, GPX4.

Transcription factor TCF3 promotes bladder cancer development via TMBIM6-Ca2+-dependent ferroptosis

TMBIM6, a Ca2+ channel-like protein, shows an increased expression in numerous types of cancer. However, no study has reported its role in bladder cancer. This study aimed to explore the roles and mechanisms of TMBIM6 in bladder cancer. TMBIM6, ferroptosis-related proteins (GPX4, SLC7A11, and FTH1), and calmodulin (CaM) expressions in bladder cancer and paracancerous tissues were obtained by immunohistochemistry. The bladder cells were overexpressed or silenced with TCF3/TMBIM6 with ferroptosis inducer (Erastin)/Ca2+ blocker (BAPTA-AM) to investigate the effects on Ca2+-dependent ferroptosis and other functions. Finally, tumorigenicity was validated in nude mice. TMBIM6 and ferroptosis-related proteins were up-regulated in bladder cancer tissues, but CaM was downregulated. TMBIM6 overexpression enhanced proliferation, invasion, migration, GSH/GPX4 levels, and ferroptosis resistance while suppressing MDA, Fe²⁺, and lipid ROS in bladder cancer cells, effects reversed by Erastin. TCF3 was up-regulated in cancer and enriched in Ca2+ and ferroptosis-related pathways. TCF3 directly interacted with TMBIM6 and transcriptionally activated TMBIM6 expression. Both TCF3 and TMBIM6 overexpression exhibited comparable effects in modulating ferroptosis and other cellular processes, whereas TMBIM6 knockdown effectively reversed these phenotypic alterations. In addition, silencing TCF3 upregulated Ca2+ and CAM levels, while BAPTA-AM reversed these changes. In vivo, ov-TCF3 promoted tumor volume, weight, and TMBIM6 expression, and inhibited Ca2+ concentration, while Erastin reversed these changes. Our findings demonstrate that TCF3 facilitates bladder cancer progression through the enhancement of TMBIM6-Ca2+-mediated ferroptosis resistance. Both TCF3 and TMBIM6 emerge as promising biomarkers and therapeutic targets for bladder cancer intervention.

AKR1C3 enhances radioresistance in esophageal adenocarcinoma via inhibiting ferroptosis through suppressing TRIM21-mediated ubiquitination of HSPA5

Esophageal adenocarcinoma (EAC) is the predominant subtype of esophageal cancer (EC) in high-income countries, and radioresistance is one of the key factors for the poor prognosis. In this study, we successfully established a radioresistant EAC in vitro model. Aldo-keto reductase 1C3 (AKR1C3) was identified as a promising regulator of radioresistance by RNA-seq analysis and subsequent functional studies. Through integrated analyses of scRNA-seq and TCGA datasets, we found that AKR1C3 was likely to enhance radioresistance by inhibition of ferroptosis. Indeed, analysis of the lipid ROS level by C11-Bodipy staining and the result of transmission electron microscopy revealed that AKR1C3 could prevent EAC cells from ferroptosis. Mechanistically, AKR1C3 binds to the nucleotide-binding domain of HSPA5, thereby inhibiting the E3 ligase TRIM21-induced ubiquitin-dependent proteasomal degradation of HSPA5, which further stabilizes GPX4, thus inhibiting ferroptosis. Importantly, AKR1C3 inhibitor resensitized the EAC patient-derived organoids to radiotherapy. In conclusion, this study highlights AKR1C3 as a regulator of radioresistance and a potential therapeutic target in EAC.

Picropodophyllin induces ferroptosis via blockage of AKT/NRF2/SLC7A11 and AKT/NRF2/SLC40A1 axes in hepatocellular carcinoma as a natural IGF1R inhibitor.

Picropodophyllin induces ferroptosis via blockage of AKT/NRF2/SLC7A11 and AKT/NRF2/SLC40A1 axes in hepatocellular carcinoma as a natural IGF1R inhibitor.

Drying methods affect nutritional value, amino acids, bioactive compounds, and in vitro function of extract in mulberry leaves.

Drying methods affect nutritional value, amino acids, bioactive compounds, and in vitro function of extract in mulberry leaves.

Gestational and lactational exposure to DEHP triggers ACSL4/TFR-mediated hippocampal neuronal ferroptosis via YAP activation: Implication for the neurocognitive disorders in male offspring.

Gestational and lactational exposure to DEHP triggers ACSL4/TFR-mediated hippocampal neuronal ferroptosis via YAP activation: Implication for the neurocognitive disorders in male offspring.

CBX5 loss drives Pl3Kδ inhibitor resistance in mantle cell lymphoma and propolis restores sensitivity by inducing CBX5-mediated ferroptosis.

CBX5 loss drives Pl3Kδ inhibitor resistance in mantle cell lymphoma and propolis restores sensitivity by inducing CBX5-mediated ferroptosis.

The role of HSPB1 in modulating ferroptosis in pancreatic cancer via the TP53/SLC7A11/GPX4 axis

PurposeThis study investigates the role of HSPB1 in pancreatic cancer, particularly its impact on cell proliferation and migration through ferroptosis regulation and interaction with TP53Materials and MethodsHSPB1 expression was analyzed using BioGPS and GEPIA databases. BxPC-3 cell lines with stable HSPB1 overexpression and knockdown were created via plasmid transfection and siRNA. The study examined HSPB1's effect on TP53 protein levels and its role in ferroptosis using TP53 agonists and inhibitors.ResultsHSPB1 mRNA levels were significantly elevated in pancreatic cancer tissues, and both mRNA and protein levels were notably upregulated in cancer cell lines. HSPB1 overexpression promoted BxPC-3 cell proliferation and migration, while silencing HSPB1 reduced these effects. High HSPB11 expression increased the levels of SLC7A11 and GPX4, while HSPB1 knockdown inhibited their expression. Transmission electron microscopy (TEM) showed that HSPB1 overexpression alleviated erastin-induced cellular damage. Although HSPB1 did not significantly affect TP53 mRNA levels, it reduced the degradation of TP53 protein, thereby enhancing the expression of SLC7A11 and GPX4 and reducing ferroptosis. The TP53 agonist significantly attenuated the effects of HSPB1 overexpression on SLC7A11 and GPX4 expression and partially restored TP53 expression. The TP53 inhibitor reversed the decrease in SLC7A11 and GPX4 expression caused by HSPB1 silencing and reduced the elevated levels of ROS and free iron. Moreover, HSPB1 overexpression reduced lipid ROS production. ConclusionHSPB1 promotes pancreatic cancer progression by suppressing TP53 signaling and increasing SLC7A11 and GPX4 expression, attenuating ferroptosis. These insights suggest HSPB1 as a potential therapeutic target, warranting further development of specific inhibitors.Graphical abstractThe figure illustrates the mechanism by which HSPB1 promotes pancreatic cancer progression by inhibiting ferroptosis. HSPB1 regulates the TP53 signaling pathway, resulting in downstream effects on key ferroptotic regulators. Specifically, HSPB1 suppresses TP53, which in turn modulates the expression of SLC7A11 and GPX4. These changes in the expression of SLC7A11 and GPX4 inhibit ferroptosis, a form of regulated cell death. The inhibition of ferroptosis ultimately promotes the survival and proliferation of pancreatic cancer cells, contributing to tumor progression.

Hypoxia/reoxygenation-induced Glycolysis Mediates Myocardial Ischemia-reperfusion Injury Through Promoting the Lactylation of GPX4.

Myocardial ischemia-reperfusion injury (MIRI) is an injury mechanism of myocardial infarction, related to ferroptosis and glycolysis. Lactate produced by glycolysis promotes protein lactylation. This study aimed to investigate the correlation between glycolysis, ferroptosis, and GPX4 lactylation in MIRI. Hypoxia/reoxygenation (H/R) increased glucose uptake, lactate production, ECAR, OCR, LDH release, lipid ROS, Fe2+, GSH, MDA contents, and cell apoptosis, and decreased GSH level in the H9C2 cells, suggesting H/R promoted glycolysis and ferroptosis. 2-DG treatment relieved the H/R-induced injury, while lactate treatment aggravated it. Besides, 2-DG suppressed lactylation of GPX4 at K218 and K228 sites and increased its protein stability. GPX4 overexpression relieved the injury caused by H/R, and alleviated cardiac injury, decreased cardiomyocyte ferroptosis in heart tissues of MIRI rats. In conclusion, GPX4 lactylation facilitated H/R-induced cardiomyocyte injury and aggravated MIRI in rats. Our findings provided new insight into targeting glycolysis and GPX4 lactylation as therapeutic strategies of MIRI.

Food-derived compounds targeting ferroptosis for cancer therapy: from effects to mechanisms.

Ferroptosis is distinctive type programmed cell death. Tumor cells, with their higher iron levels, render them more susceptible to ferroptosis Inducing ferroptosis can activate immune cells, regulate immune evasion, and inhibit the biology activity of cancer cells. Therefore, ferroptosis-induced cancer cell death could become a promising approach for cancer treatment. Dietary compounds are an important source for drug discovery, and there has been an increasing amount of literature on food-derived ferroptosis inducers and their applications in cancer treatment. This review provides an overview of the regulatory mechanisms involved in ferroptosis, explores the mechanisms by which dietary compounds act as ferroptosis inducers, and discusses their effects on various cancers, especially by accumulating lipid ROS and overloading Fe2+, along with inhibiting GPX4 expression to promote ferroptosis in tumors. Additionally, the latest advancements in new methods for inducing ferroptosis, including the use of nanomaterials, are also summarized. Finally, the challenges and opportunities of developing dietary compounds as ferroptosis inducers are discussed, focusing on the discovery of new targets, enhancing selectivity, as well as reducing toxicity and the recurrence of side effects. As far as we know, this is the first comprehensive and systematic summary on the anticancer effects and mechanisms of food-derived ferroptosis inducers.

Zileuton protects against arachidonic acid/5-lipoxygenase/leukotriene axis-mediated neuroinflammation in experimental traumatic brain injury.

Traumatic brain injury (TBI) is a leading cause of death and disability globally. Several studies have shown that 5-lipoxygenase (5-LOX) inhibition reduces leukotriene (LT) release and the inflammatory response, attenuating the development of respiratory diseases, myocardial infarction, and ischemic cerebral injury. However, its role in the pathophysiology of TBI remains unclear. Controlled cortical impact injury was induced to construct a mouse model of TBI. Pericontusional brain tissue samples from sham and TBI mice at 7 days after injury were used for RNA-seq analysis. Altered gene enrichment following TBI, based on Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, was quantified through real-time polymerase chain reaction (RT-PCR). Immunocytochemistry, Western blotting, and single-cell sequencing experiments were also performed to analyze 5-Lox protein expression. Arachidonic acid (AA) was detected through liquid chromatography mass spectrometry/mass spectrometry. Enzyme-linked immunosorbent assay was used to detect LTB4 release after TBI with or without zileuton treatment. Brain damage, blood-brain barrier disruption, and neuronal apoptosis were detected through histological examination. Neurological outcomes were determined through rotarod and fear conditioning tests. TBI induced significant upregulation of genes related to the AA metabolic pathway, particularly the AA/5-LOX/LT axis, as verified by RT-PCR. AA and LTB4 production increased significantly after TBI. The expression levels of Pla2g4a, which hydrolyses phospholipids to release AA, and 5-Lox, which in turn act downstream to convert AA to LT, were dramatically upregulated up to 7 days after TBI. 5-LOX accumulated in the cytoplasm of activated ameboid microglial cells. In vivo, 5-LOX inhibition with zileuton blocked LT release and reduced microglial activation and the production of inflammatory cytokines, including Il-1β, Ccl7, Spp1, Ccr1, Ccl2, and Il-10. Zileuton also reduced TBI-induced lipid ROS and neuronal cell apoptosis, ameliorating brain damage compared to the vehicle group and improving neurological outcomes after TBI. Mechanically, TBI-induced LT upregulation may stimulate BV2 microglial activation through the ERK, NF-κB, and Akt pathways. Our findings demonstrated the role of 5-LOX in TBI and its potential as a therapeutic target in TBI treatment.

Silencing ribosome biogenesis regulator 1 homolog (RRS1) inhibits angiogenesis and cisplatin resistance of lung cancer cells by activating ferroptosis mediated by p53 pathway.

Silencing ribosome biogenesis regulator 1 homolog (RRS1) inhibits angiogenesis and cisplatin resistance of lung cancer cells by activating ferroptosis mediated by p53 pathway.

Targeting RPLP2 Triggers DLBCL Ferroptosis by Decreasing FXN Expression.

Background/Objectives: Ribosomal Protein Lateral Stalk Subunit P2 (RPLP2), an important ribosomal protein, is mainly involved in modulating protein synthesis and plays an essential role in the carcinogenesis of many cancers. However, its precise impact on diffuse large B-cell lymphoma (DLBCL) remains unknown. Methods: This study utilized siRNA to knock down RPLP2, aiming to investigate its role in DLBCL progression. RT-qPCR and immunohistochemistry (IHC) were employed to assess RPLP2 and frataxin (FXN) expression levels in DLBCL. CCK8 and colony formation assays measured cell proliferation inhibition upon RPLP2 deletion, while transwell migration assays analyzed reduced cell motility. Lipid ROS and iron assays quantified ferroptosis markers to elucidate RPLP2's regulation of FXN-mediated ferroptosis. Xenograft mouse models validated tumor suppression effects in vivo. Results: Here, we reveal that elevated RPLP2 expression is significantly correlated to unfavorable prognosis in DLBCL patients. In addition, we demonstrate that RPLP2 deletion dramatically reduces the cell proliferation and migration of DLBCL. Besides, knockdown of RPLP2 triggers ferroptosis via regulating ferroptosis suppressor FXN activity. Moreover, we discover that Destruxin b could target RPLP2 to suppress the development of DLBCL. Lastly, the combination of Destruxin b with Dox remarkably improves the anti-tumor effect. Conclusions: In general, the present study reveals the oncogenic role of RPLP2 in DLBCL, uncovers an unrecognized regulatory axis of ferroptosis, and identifies a specific inhibitor targeting RPLP2 to restrain DLBCL progression, suggesting that RPLP2 could be a potential target for DLBCL treatment.

Silencing NRF2 enhances arsenic trioxide-induced ferroptosis in hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, with high mortality rates partially due to limited therapeutic options and drug resistance. Arsenic trioxide (ATO), a compound clinically proven for acute promyelocytic leukemia (APL), has garnered attention for its emerging efficacy in solid tumors, including HCC. However, the molecular mechanisms driving ATO's antitumor activity in HCC remain incompletely understood. In this study, we aimed to elucidate the ferroptosis-dependent effects of ATO on HCC and and propose a potential therapeutic strategy. The response of HCC cells to ATO was evaluated using cell viability, wound healing, colony formation, Transwell migration assays, and cell cycle analysis. ATO-induced ferroptosis was assessed by measuring lipid peroxidation (via C11-BODIPY staining), intracellular iron levels, and malondialdehyde (MDA) production. Western blotting was performed to quantify protein levels of NRF2, HO-1, SLC7A11, and GPX4; immunofluorescence staining was employed to determine NRF2 subcellular localization. ATO exhibited significant cytotoxicity and inhibited the progression of HCC cells. Treatment with ATO resulted in a notable increase in lipid ROS and MDA levels, which were subsequently reversed by the ferroptosis inhibitors Fer-1 and DFO. Mechanistically, ATO induced ferroptosis by inhibiting GPX4. Furthermore, NRF2 and its downstream targets, HO-1 and SLC7A11, were upregulated during ferroptosis. NRF2 knockdown enhanced lipid peroxidation and ATO-induced cell death. ATO significantly promoted ferroptosis in HCC cells, and NRF2 knockdown enhanced the cytotoxic effects of ATO.

Inhibition of TPI1 Sensitizes Cisplatin-Resistant Oral Cancer to Ferroptosis

Background: Iron metabolism has emerged as a critical factor in cancer biology, with elevated intracellular iron levels contributing to increased oxidative stress and tumorigenesis. However, the molecular determinants governing ferroptosis sensitivity remain incompletely understood. Triosephosphate isomerase 1 (TPI1), a key glycolytic enzyme, has been implicated in cancer progression, but its role in ferroptosis regulation, particularly in the context of chemoresistance, is largely unexplored. In this study, we investigated the impact of TPI1 silencing on ferroptosis in cisplatin-resistant oral squamous cell carcinoma (OSCC), aiming to elucidate its mechanistic role and therapeutic potential. Methods: We conducted in vitro and in vivo analyses to evaluate the functional consequences of TPI1 knockdown in cisplatin-resistant OSCC cell lines and tumor xenograft models. The effects of TPI1 silencing and/or cisplatin treatment were assessed with respect to cell proliferation, migration, and invasion, along with ferroptosis-associated markers, including lipid ROS, free iron levels, lipid peroxidation, and the expression of key ferroptosis-related genes. Additionally, we analyzed the clinical relevance of TPI1 expression in human OSCC tissue samples, examining its association with clinicopathological features and patient prognosis. Results: TPI1 was found to be significantly upregulated in both OSCC tissues and cell lines, and high TPI1 expression correlated with poor clinical outcomes. Multivariate analysis identified TPI1 as an independent prognostic factor for tumor progression. Functionally, TPI1 knockdown suppressed OSCC cell proliferation, migration, and invasion, while its overexpression enhanced these oncogenic behaviors. Mechanistically, silencing TPI1 led to increased intracellular ROS accumulation, elevated free iron, and enhanced lipid peroxidation, collectively promoting ferroptotic cell death in cisplatin-resistant OSCC cells. In vivo, TPI1 depletion resulted in marked tumor growth inhibition and synergized with cisplatin to further suppress tumor burden in xenograft models. Moreover, TPI1 silencing disrupted the epithelial–mesenchymal transition (EMT), a key driver of cancer metastasis and drug resistance. Conclusions: Our study reveals a previously unrecognized role of TPI1 in protecting oral cancer cells from ferroptosis, especially in the setting of cisplatin resistance. These findings suggest that TPI1 not only contributes to tumor aggressiveness but also mediates resistance to ferroptosis. Targeting TPI1 may therefore represent a promising therapeutic strategy to overcome chemoresistance and enhance ferroptosis-based therapies in oral cancer.

A CoQ10 analog ameliorates cognitive impairment and early brain injury after subarachnoid hemorrhage by regulating ferroptosis and neuroinflammation

A CoQ10 analog ameliorates cognitive impairment and early brain injury after subarachnoid hemorrhage by regulating ferroptosis and neuroinflammation

PSMD14/E2F1 Axis-Mediated CENPF Promotes the Metastasis of Triple-Negative Breast Cancer Through Inhibiting Ferroptosis.

The metastasis of triple-negative breast cancer (TNBC) usually contributes to the failure of treatment. Centromere Protein F (CENPF) can induce proliferation and metastasis in TNBC. Nevertheless, the upstream mechanism of CENPF in BC remains unclear. Western blot and RT-qPCR were employed for testing the levels of PSMD14, E2F1, and CENPF, and cell migration was assessed using the Transwell assay. Additionally, the CCK8 assay was applied to investigate cell viability, and C11-BODIPY 581/591 was applied to assess the lipid ROS level. ChIP and dual luciferase assays were used to examine the association between E2F1 and the CENPF promoter. The interaction between PSMD14 and E2F1 was verified using Co-IP. Knockdown of CENPF could significantly inhibit migration and invasion in TNBC cells. In addition, the silencing of CENPF aggravated arachidonic acid metabolism-induced ferroptosis in TNBC cells. Meanwhile, E2F1 knockdown greatly inhibited the expressions of CENPF and attenuated TNBC cell invasion and migration by decreasing its binding with the CENPF promoter. More importantly, PSMD14 could suppress arachidonic acid metabolism-induced ferroptosis in TNBC cells through the E2F1/CENPF axis. The PSMD14/E2F1 axis-mediated CENPF could promote the metastasis of TNBC by inhibiting arachidonic acid metabolism-induced ferroptosis. This research might bring novel insights into discovering methods for alleviating tumor metastasis in TNBC.

Salidroside can protect against ferroptosis in cardiomyocytes and may be related to the regulation of GGT1.

Ferroptosis, an iron-dependent cell death mechanism driven by lipid peroxidation, represents a novel therapeutic target for myocardial injury. Salidroside (SAL), a natural bioactive compound derived from Rhodiola rosea, exhibits cardioprotective effects through multi-target mechanisms with minimal adverse effects, yet its precise role in ferroptosis regulation remains unclear. This study systematically investigated SAL's anti-ferroptotic effects using in vitro (RSL3-induced H9C2 cardiomyocytes) and in vivo (DOX-induced myocardial injury mouse model) approaches. SAL treatment significantly enhanced cardiomyocyte viability by attenuating ferroptotic hallmarks, including lipid ROS accumulation, iron overload, lipid peroxidation, and mitochondrial dysfunction. Transcriptomic analysis revealed SAL-mediated modulation of DNA replication/repair, cell cycle regulation, protein autophosphorylation, drug ADME processes, and glutathione metabolism-a critical pathway in ferroptosis. Molecular docking identified γ-glutamyltransferase 1 (GGT1) as a high-affinity SAL target, linking drug metabolism and glutathione homeostasis. In MI mice, SAL downregulated GGT1 expression while restoring ferroptosis-related biomarkers: upregulating GPX4 and reducing SLC7A11/LC3II levels. Mechanistically, SAL suppresses ferroptosis through dual regulation of GGT1: (1) enhancing glutathione synthesis via GGT1 inhibition and (2) potentiating GPX4-mediated antioxidant defense. These findings establish GGT1 as a pivotal therapeutic target for SAL's cardioprotection, providing a mechanistic basis for its clinical application in ferroptosis-associated cardiovascular diseases.

NDUFA8 promotes cell viability and inhibits ferroptosis and cisplatin sensitivity by stabilizing Fe-S clusters in cervical cancer.

Cervical cancer (CC) ranks among the primary causes of cancer fatalities in women, with cisplatin (DDP) resistance significantly impacting clinical outcomes. NADH dehydrogenase (ubiquinone) FA8 (NDUFA8) is significantly upregulated in CC tissues and correlates with lower survival rates, but its role in cisplatin sensitivity in CC is still unclear. NDUFA8 silencing inhibited CC cell viability, promoted ferroptosis, evidenced by increased Fe2+ and lipid ROS levels, along with decreased levels of ATP and reduced activities of complex I, aconitase (ACO), and xanthine oxidase (XO). However, overexpression of NDUFA8 promoted CC cell viability, inhibited ferroptosis, and increased levels of ATP and activities of complex I, ACO, and XO in ferric ammonium citrate (FAC) or rotenone-treated CC cells. NDUFA8 expression showed a negative correlation with the DDP therapy response in CC tissues and cell lines. However, in CC tissues, NDUFA8 expression was positively associated with ACO and XO activities. In in vivo experiments, the overexpression of NDUFA8 diminished the anti-tumor effects of DDP, which was counteracted by FAC. NDUFA8 promotes cell viability and inhibits ferroptosis and DDP sensitivity by stabilizing Fe-S clusters in CC.