Activating the cGAS-STING pathway presents a promising strategy to enhance the innate immunity and combat the immunosuppressive tumor microenvironment. One key mechanism for triggering this pathway involves the release of damaged DNA fragments caused by nuclear DNA damage. However, conventional cGAS-STING agonists often suffer from limited nucleus-targeting efficiency and potential biotoxicity. In this study, we develop a novel nucleus-targeting theranostic nanoplatform designed to synergistically activate the cGAS-STING pathway through the combination of photodynamic therapy (PDT) and cisplatin chemotherapy for orthotopic bladder cancer treatment. The nanoplatform integrates a new high-performance type-I photosensitizer with near-infrared-II emission, a TATSA peptide for enhanced nuclear targeting, and a biosafe platinum (IV) cisplatin prodrug. Upon NIR laser irradiation, the nanoagent delivers synergistic nucleus-targeted PDT and chemotherapy, causing substantial DNA damage and the release of double-stranded DNA, which subsequently activates the cGAS-STING pathway and triggers potent immunomodulation. This activation promotes dendritic cells maturation, enhances cytotoxic T infiltration, and facilitates the formation of memory T cells, leading to immune microenvironment remodeling, and long-lasting immune memory, thus effectively inhibiting orthotopic bladder tumors and reducing the risk of metastasis. These findings highlight the substantial potential of this strategy to overcome the limitations of current immunotherapies by leveraging nucleus-targeted PDT to activate the cGAS-STING pathway for cancer treatment.

Cisplatin is a common chemotherapy agent for solid tumors but severe nephrotoxicity limits its application, with no effective pharmacological treatments. Organic cation transporter 2 (OCT2) is involved in cisplatin uptake in kidneys. This study aimed to find drugs with promising clinical applications that could prevent cisplatin-induced acute kidney injury (Cis-AKI) by inhibiting OCT2.

The mRNA level of OCT2 was examined in human induced pluripotent stem cells (iPSCs) from Cis-AKI patients and paired non-AKI patients. The association between OCT2 and Cis-AKI was investigated by HEK293FT cells and kidney organoids. We screened potential compounds exhibiting protective effects against Cis-AKI in US Food and Drug Administration-approved drugs through virtual screening and activity screening. Subsequently, we determined the effects of these compounds on OCT2 expression, cisplatin uptake, and apoptosis in cells, kidney organoids and mice. A549 and HeLa cells were adopted to observe the influence of drugs on the anti-tumor function of cisplatin.

Compared to non-AKI patients, the OCT2 mRNA levels of iPSCs from Cis-AKI patients were elevated. OCT2 exhibits similar expression patterns in kidney organoids and human kidney tissues. Furthermore, the overexpression of OCT2 in kidney organoids and HEK293FT cells exacerbated the injury caused by cisplatin. Carvedilol and cimetidine were identified as potent OCT2 inhibitors by drug screening. Further analysis revealed that the pretreatment of carvedilol or cimetidine downregulated OCT2, reduced cisplatin uptake, and alleviated cisplatin-induced apoptosis, but the combination of the two drugs didn't further improve these outcomes. Additionally, carvedilol and cimetidine didn't compromise the cisplatin-induced cell death in A549 and HeLa cells.

Our study confirmed that carvedilol and cimetidine exert protective effects against Cis-AKI by inhibiting OCT2, without altering the anti-tumor effects of cisplatin.

In this article, the antitumor and antiproliferative activity of three Ru(III) complexes, [RuIII(Salen)(PPh3)Cl] (RuSalen), [RuIII(Salphen)(PPh3)Cl] (RuSalphen), and [RuIII(Salpn)(PPh3)Cl] (RuSalpn) (H2Salen, H2Salphen and H2Salpn are the Schiff bases obtained by the condensation between salicylaldehyde and ethylenediamine, 1,2-phenylenediamine, and 1,3-diaminopropanne, respectively) and their precursor, [RuII(PPh3)3Cl2], were investigated against laboratory-cultured tumor cell lines: HT29 (human colorectal carcinoma), Saos-2 (human osteogenic sarcoma), HeLa (human cervical carcinoma), RST (rat transplantable sarcoma), and the non-tumor cell line Lep3 (embryonal human fibroblasts). It was found that all the cancer cell lines investigated were effectively dose-dependently inhibited in their growth by the Ru(III) complexes, while the non-tumor cell line Lep3 was the least affected by their cytotoxic effect. The Annexin V assay revealed that the Ru(III) complexes determined the occurrence of apoptosis in all cell lines tested, in a dose-dependent manner. RuSalpn exhibited the strongest ability to reduce tumor cell survival and proliferation, with efficacy that is either superior to or comparable to that of well-established clinical oncology agents such as cisplatin, oxaliplatin, epirubicin, and paclitaxel. The experiments revealed a cell-specific response, with varying degrees of sensitivity to the tested substances across different cell lines. RuSalpn demonstrated the strongest cytotoxic effect in the HT29 cell line, while RuSalen, RuSalphen showed the highest activity against RST cells. It was found that RuSalphen (≥7.0 μM) significantly inhibited cell migratory activity in the HT29 cell line, while in the RST cell line, RuSalen (≥37.6 μM), RuSalphen (≥14.0 μM), and RuSalpn (≥36.8 μM) demonstrated a strong inhibitory effect on cell migration.

Cisplatin (DDP) resistance in non-small cell lung cancer (NSCLC) is a common cause of treatment failure and a significant contributor to increased mortality. To tackle this issue, the integration of traditional Chinese medicine with chemotherapy has been proposed as a promising approach. The potential synergistic effect of combining polyphyllin VII (PPVII) and DDP in overcoming DDP resistance in NSCLC cells has not been thoroughly investigated yet. In this study, H1299 cells were exposed to gradient concentrations of PPVII and DDP to determine their 50% inhibitory concentration values, and the most effective concentration was applied in subsequent experiments. The combination of PPVII and DDP was evaluated for its effects on H1299 cell proliferation, apoptosis, viability, and the expression of proteins linked to apoptosis and ferroptosis. To further elucidate the underlying mechanisms, the impact of the combination on DNA damage in H1299 cells was also examined. Our results demonstrated that PPVII significantly potentiated the antitumor effects of DDP in H1299 cells in a dose-dependent manner (p < 0.05). Furthermore, PPVII was observed to work synergistically with DDP to suppress proliferation and promote apoptosis in H1299 cells (p < 0.05). Western blotting analysis proved that the combination treatment upregulated proapoptotic proteins (B-cell lymphoma 2-associated X protein, cleaved-caspase 3 and cleaved-PARP), downregulated antiapoptotic protein (Bcl-2), and promoted ferroptosis-associated proteins (long-chain acyl-coenzyme A synthase 4 and NADPH oxidase 4) as well as DNA damage-associated protein (γH2AX) (p < 0.05). Overall, the combination of PPVII and DDP significantly enhanced antitumor activity in H1299 cells through the modulation of DNA damage and ferroptosis, suggesting its potential as an effective therapeutic approach against DDP-resistant NSCLC.

Due to their role in excretion, renal proximal tubular cells are susceptible to damage by toxic metabolites and xenobiotics. The regenerative capacity of the kidney allows for the replacement of damaged cells, a process involving differentiation programs. However, kidney function tends to decline, suggesting that the replacement cells may not achieve full functionality. To understand possible causes of this decline, we investigated effects of nephrotoxins and oxidants on the differentiation of induced pluripotent stem cells (iPSC) into proximal tubular epithelial-like cells (PTELC). Proliferation, apoptosis, senescence, and expression of oxidative defense genes were analyzed in iPSC, differentiating and differentiated cells treated with cisplatin (CisPt, up to 45 µM), cyclosporin A (CycA, up to 12 µM), and the oxidants menadione (Mena, up to 50 µM) and tert-butylhydroquinone (tBHQ, up to 50 µM). We found that differentiating cells were most sensitive to oxidants and showed increased sensitivity to CisPt, whereas all differentiation stages showed similar sensitivity to CycA. Both oxidative stress and CisPt triggered apoptosis in all differentiation stages, whereas CycA mainly induced senescence. Treatment during differentiation resulted in long-term effects on gene expression in differentiated cells. While oxidants had no effect on transport function of differentiated cells, CisPt and CycA impaired albumin uptake. Our data suggest a substantial sensitivity of differentiating cells to nephrotoxins and oxidants, an aspect that could potentially interfere with regenerative processes.

Providing an unbiased and comprehensive view of the DNA damage response in cells is critical in genotoxicity screening to identify substances that cause diverse types of DNA damage. Considering that S. cerevisiae is one of the most well-characterized model organisms in molecular and cellular biology, we created a map of the DNA damage response network containing the reported signaling pathways in yeast cells programmed to constitutively respond to DNA damage. A collection of GFP-fused S. cerevisiae yeast strains treated with typical genotoxic agents illuminated the cellular response to DNA damage, thereby identifying 15 protein biomarkers encompassing all eight documented DNA damage response pathways. Three statistical and one deep learning models were proposed to interpret the quantitative molecular toxicity end point, i.e. protein effect level index (PELI), by introducing weights of 15 biomarkers in genotoxicity assessment. The method based on standard deviation exhibited the best performance, with an R 2 of 0.916 compared to the SOS/umu test and an R 2 of 0.989 compared to the comet assay. The GFP-fused yeast-based proteomic assay has minute-level resolution of pathway activation data. It provides a concise alternative for fast, efficient, and mechanistic genotoxicity screening for various environmental and health applications.

Regulated cell death is integral to sculpting the developing brain, yet the relative contributions of extrinsic apoptosis and necroptosis remain unclear. Here, we leverage single-cell mass cytometry (CyTOF) to characterize the cellular landscape of the mouse telencephalon in wild-type (WT), RIPK3 knockout (RIPK3 KO), and RIPK3/Caspase-8 double knockout (DKO) mice. Strikingly, combined deletion of RIPK3 and Caspase-8 leads to a 12.6% increase in total cell count, challenging the prevailing notion that intrinsic apoptosis exclusively governs developmental cell elimination. Detailed subpopulation analysis reveals that DKO mice display selective enrichment of Tbr2⁺ intermediate progenitors and endothelial cells, underscoring distinct, cell type-specific roles for extrinsic apoptotic and necroptotic pathways. These findings provide a revised framework for understanding the coordinated regulation of cell number during telencephalic development and suggest potential mechanistic links to neurodevelopmental disorders characterized by aberrant cell death.

Ovarian cancer is one of the leading causes of cancer-related deaths in women, with limited progress in treatments despite decades of research. Common treatment protocols rely on surgical removal of tumors and chemotherapy drugs, such as paclitaxel and carboplatin, which are capable of reaching cancer cells throughout the body. However, the effectiveness of these drugs is often limited due to toxic reactions in patients, nonspecific drug distribution affecting healthy cells, and the development of treatment resistance. In this study, we introduce a polybasic nanogel system composed of poly(diethylaminoethyl methacrylate-co-cyclohexyl methacrylate)-g-poly(ethylene glycol) designed for the targeted co-delivery of paclitaxel and carboplatin directly to ovarian cancer cells. These nanogel systems can respond to the cellular microenvironment to achieve controlled, on-demand drug release, reducing off-target effects and enhancing therapeutic uptake. Additionally, we investigated nanoparticle degradation and controlled drug release as a function of various crosslinkers, including tetraethylene glycol dimethacrylate, bis(2-methacryloyl)oxyethyl disulfide, poly(lactic acid)-b-poly(ethylene glycol)-b-poly(lactic acid)dimethacrylate, and polycaprolactone dimethacrylate. Our results, using OVCAR-3 human ovarian cancer cells, demonstrated that this dual-delivery system outperformed free drugs in inducing cancer cell death, representing a promising advance in the field of nanoparticle-based therapies for ovarian cancer. By loading two chemotherapeutic agents into a single, environmentally responsive particle, this approach shows the potential to overcome common resistance mechanisms and achieve more effective tumor suppression. In summary, by delivering chemotherapy more precisely, it may be possible to enhance therapeutic outcomes while minimizing toxicity and nonspecific drug distribution, ultimately improving patient quality of life.

Lung cancer is a leading cause of cancer-related mortality worldwide, largely due to its heterogeneity and intrinsic drug resistance. Malignant pleural effusions (MPEs) provide diverse tumor cell populations ideal for studying these complexities. Although chemotherapy and targeted therapies can be initially effective, subpopulations of cancer cells with phenotypic plasticity often survive treatment, eventually developing resistance. Here, we integrated single-cell isolation and three-dimensional (3D) spheroid culture to dissect subclonal heterogeneity and drug responses, aiming to inform precision medicine approaches. Using A549 lung cancer cells, we established a cisplatin-resistant line and isolated three resistant subclones (Holoclone, Meroclone, Paraclone) via single-cell sorting. In 3D spheroids, Docetaxel and Alimta displayed higher IC50 values than in 2D cultures, suggesting that 3D models better reflect clinical dosing. Additionally, MPE-derived Holoclone and Paraclone subclones exhibited distinct sensitivities to Giotrif and Capmatinib, revealing their heterogeneous drug responses. Molecular analyses confirmed elevated ABCB1, ABCG2, cancer stem cell (CSC) markers (OCT4, SOX2, CD44, CD133), and epithelial-mesenchymal transition (EMT) markers (E-cadherin downregulation, increased Vimentin, N-cadherin, Twist) in resistant subclones, correlating with enhanced migration and invasion. This integrated approach clarifies the interplay between heterogeneity, CSC/EMT phenotypes, and drug resistance, providing a valuable tool for predicting therapeutic responses and guiding personalized, combination-based lung cancer treatments.

Platinum chemotherapy is part of every second anticancer treatment regimen. However, its application is limited by severe side effects and drug resistance. The combination of platinum-based chemotherapeutics with EGFR inhibitors has shown remarkable synergism in clinical treatment. To enhance the tolerability of this combination, we designed a novel multi-action oxaliplatin-based platinum(iv) complex with an EGFR-inhibiting moiety (KP2749). KP2749 releases two independent cytotoxic agents upon reduction: oxaliplatin and the EGFR inhibitor KP2187, which was selected for its strong intrinsic fluorescence that became quenched upon complexation to metal ions. In particular, KP2749 demonstrated high stability and specific KP2187 release, with quenched fluorescent properties in its intact form, facilitating the investigation of its intracellular reduction. Notably, by exploiting its fluorescence, we demonstrated that intact KP2749 itself exhibited EGFR-inhibitory properties. Furthermore, subsequent experiments indicated that our complex was able to overcome resistance to oxaliplatin and EGFR inhibitors in vitro and in xenograft models in vivo. These effects were not only based on EGFR inhibition and DNA damage, but also improved cellular drug uptake. Finally, in silico docking analysis confirmed that the intact KP2749 complex had EGFR-binding properties, which were different from free KP2187. Consequently, these data suggested that the coordination of EGFR inhibitors to metal cores (like platinum) allow the fine-tuning of their EGFR-targeting properties. In conclusion, this study not only presents a new potential anticancer drug but also offers a novel fluorescent tool to study the intracellular drug release kinetics of platinum(iv) complexes.

Drug resistance is a major cause of cancer recurrence and poor prognosis. The innovative design and synthesis of inhibitors to target drug-resistance-specific proteins is highly desirable. However, challenges remain in precisely adjusting their conformation and stereochemistry to adapt the chiral regions of target proteins. Herein, using a stepwise programmable modular assembly approach, we precisely engineered two pairs of homochiral dinuclear Ir(III) metallohelices (Λ2S4-Hbpy and Δ2R4-Hbpy, Δ2S4-Hbpy and Λ2R4-Hbpy) functionalized with flexible dithiourea linkages. The resulting homochiral metallohelices exhibited significant chirality-dependent photocytotoxicities, and the enhanced structural compatibility of Δ2S4-Hbpy with the target cyclin-dependent kinase 1 (CDK1) contributed to its superior photodynamic therapy efficacy, achieving an outstanding photocytotoxicity index (PI) value of 2.3×104. Interestingly, emerging as a critical mediator in the development of oxaliplatin resistance, CDK1 targeting by Δ2S4-Hbpy achieved enhanced cellular uptake, anticancer activity, and oncosis-mediated cell death in oxaliplatin-resistant HCT-8/L cells. Mechanistic investigations, including proteomic profiling and CDK1 gene silencing, confirmed the pivotal role of chirality-selective CDK1 targeting in reversing metallodrug resistance. This study introduces a promising platform for constructing and customizing flexible metallohelices with precise conformation and stereochemistry to target drug-resistance-specific proteins, offering innovative insights into the designability of metallodrugs to overcome drug resistance.

Platinum(IV) compounds possess distinct properties that set them apart from platinum(II) compounds. Often designed as prodrugs, they are reduced within cancer cells to their active platinum(II) form, enabling their cytotoxic effects. Their versatility also lies in their ability to be functionalized and conjugated with bioactive molecules to enhance cancer cell targeting. This report introduces new prodrugs that combine antitumor cisplatin with axially coordinated eugenol, leveraging their synergistic action to target cancer stem cells. A third bioactive ligand, 4-phenylbutyrate or octanoate, was added to further enhance biological activity, creating 'triple action' prodrugs. These new platinum(IV) prodrugs offer a novel approach to cancer therapy by improving targeting, increasing efficacy, overcoming drug resistance, and reducing tumor invasiveness while sparing healthy tissue.

A new family of ethacrynic acid-functionalized, chalcone-hydroxypyrone hybrid ruthenium(II)-arene complexes (4a-4e) have been designed, synthesis and fully characterized by 1H and 13C NMR, ESI-MS, elemental analysis, and melting point tests. The molecular structure of 3a, one of the precursor complexes, has been determined by single-crystal X-ray diffraction. The cytotoxicity of the obtained complexes toward human cancer cell lines such as HeLa, MGC803, A549, MDA-MB-231, and MCF-7 cells have been investigated by MTT assay. Whereas complexes 4d and 4e showed significantly higher cytotoxicity than cisplatin (the positive control group) and complexes 3a-3e. Moreover, complexes 4d and 4e exhibited a certain selectivity (selectivity index: 7.33 and 7.57) toward MCF-7 cells over MCF-10a normal cells. Glutathione S-transferases (GSTs) activity assay indicate that complexes 4d and 4e exhibited higher GST inhibitory activity than ethacrynic acid (EA, the best characterized GST inhibitor), consistent with their higher cytotoxicity. Further mechanistic studies showed that 4e-induced cell apoptosis may be aroused by the production of ROS, the loss of mitochondrial membrane potential and G2/M phase cell arrest in MCF-7 cells. In addition, the in vivo antitumor effect study on the xenograft mouse models of MCF-7 cells reveal that complex 4e significantly inhibited tumor growth with a higher inhibition efficiency of 68.80 %, in comparison with the groups treated with cisplatin (59.25 %). These results highlight the strong possibility to develop positively-charged, chalcone-hydroxypyrone hybrid ruthenium(II)-arene complexes funcionalized with GST inhibitor as promising anticancer agents.

This study presents the development and evaluation of triphenylphosphine-modified cyclometalated iridiumIII complexes as selective anticancer agents targeting mitochondria. By leveraging the mitochondrial localization capability of the triphenylphosphine group, these complexes displayed promising cytotoxicity in the micromolar range (3.12-7.24 μM) against A549 and HeLa cancer cells, these complexes exhibit significantly higher activity compared to their unmodified counterparts lacking the triphenylphosphine moiety. Moreover, they demonstrate improved specificity for cancer cells over normal cells, achieving selectivity index in the range of 5.46-14.83. Mechanistic studies confirmed that these complexes selectively target mitochondria rather than DNA, as shown by confocal microscopy and flow cytometry, where they accumulate to induce mitochondrial dysfunction. This disruption leads to mitochondrial membrane depolarization (MMP), elevated reactive oxygen species (ROS) levels, and activation of intrinsic apoptosis pathways. Furthermore, the complexes induce cell cycle arrest at the G2/M phase and suppress the migration of A549 cells.

Cancer remains one of the deadliest diseases worldwide, with some tumors proving difficult to treat and increasingly resistant to current therapies. Capitalizing on this, there is a need for new therapeutic agents with novel mechanisms of action. Among promising candidates, Fe(III) complexes have gained significant attention as potential chemotherapeutic agents. However, research on these compounds has been limited to a small number, leading to inefficiencies in drug discovery. This study addresses these limitations by developing a combinatorial library of 495 new Fe(III) complexes synthesized from aminophenol, hydroxybenzaldehyde, and pyridine derivatives. The compounds were screened for cytotoxicity against human breast adenocarcinoma and noncancerous fibroblasts, identifying a novel class of Fe(III) complexes with modest cancer cell selectivity. The lead compound effectively eradicated breast cancer tumor spheroids at low micromolar concentrations, highlighting the potential of this approach for rapid drug discovery.

[M(arene)(HQ)Cl] complexes (M = RuII/OsII/RhIII/IrIII; HQ = 8-hydroxyquinoline) have shown promise as anticancer agents. To assess the effect of conjugating biotin (vitamin B7) to such compounds and improve their tumor-targeting ability through interaction with the sodium-dependent multivitamin transporter (SMVT), the chlorido co-ligand was exchanged with biotinylated 6-aminoindazole. The complexes were characterized by NMR spectroscopy and mass spectrometry, and purity was determined by elemental analysis. The compounds were shown to be stable in aqueous solution but reacted in particular with biologically relevant nitrogen-donor ligands. The biotinylated organometallics were shown to be able to interact with the high-affinity biotin-binding protein streptavidin using molecular modelling. High antiproliferative activity of the biotinylated Rh complex (IC50 = 1.1-10 μM) and its chlorido precursor (IC50 = 2.1-7.0 μM) was demonstrated in human HCT116, NCI-H460, COLO 205, SW620, A2780 and A2780cis cancer cells, which feature differing levels of SMVT expression. While there was no clear relationship between the anticancer activity in cells and SMVT expression, the complexes showed similar activity in cisplatin-sensitive and -resistant cells. The most potent was the biotinylated Rh derivative which displayed low toxicity toward zebrafish embryos with >75% survival up to day 4 and after treatment with up to 32 μM complex.

Gastric cancer (GC) is a significant cancer-related cause of death worldwide. GC's most used chemotherapeutic regimen is based on platinum drugs such as cisplatin (CDDP). However, CDDP chemoresistance reduces the survival rate of advanced GC. The immune C-C chemokine receptor type 5 (CCR5) have been proposed as a pivotal factor in cancer progression since its blockade has been linked with antineoplastic effects on tumor cell proliferation; nevertheless, its role in the chemoresistance of GC has not been elucidated. This study aimed to determine the effects induced by the CCR5 using Maraviroc (MVC), a highly selective CCR5 antagonist, on CDDP-resistant AGS cells (AGS R-CDDP), tumoroids (3D tumor spheroids), and animal models.

The combined CDDP and MVC treatment reduced cell viability and inhibited tumoroid formation in AGS R-CDDP cells. The effects of the MVC/CDDP combination on apoptosis and cell cycle progression were correlated with the increase in CDDP (dose-dependent). The mRNA levels of C-C Motif Chemokine Ligand 5 (CCL5), the main ligand for CCR5, decreased significantly in cells treated with the MVC/CDDP combination. MVC in the MVC/CDDP combination improved the survival rate and biochemical parameters of CDDP-treated mice by reducing the side effects of CDDP alone.

This finding suggests that MVC/CDDP combination could be a potential complementary therapy for GC.

Platinum drugs are the most widely used chemotherapeutics to treat various tumors. Their primary mode of action is supposed to be inducing apoptosis of cancer cells via covalent binding to DNA. This mechanism has shackled the design of new platinum drugs for many years. Mounting evidence shows that many platinum complexes form non-covalent adducts with DNA or interact with proteins to exhibit significant antitumor activity, thus implying some distinct mechanisms from that of traditional platinum drugs. These unconventional examples indicate that covalent DNA binding is not the precondition for the antitumor activity of platinum complexes, and diversified reactions or interactions with biomolecules, organelles, signal pathways, or immune system could lead to the antitumor activity of platinum complexes. The atypical mechanisms break the classical DNA-only paradigm and structure-activity relationships, thus opening a wide avenue for the design of innovative platinum anticancer drugs.

Here, we report the X-ray structure of the adduct formed upon reaction of cisplatin, one of the most prescribed anticancer agents for the clinic treatment of solid tumors, with the apo-form of human serum transferrin (hTF). Two Pt binding sites were identified in both molecules of the adduct present in the crystal asymmetric unit: Pt binds close to the side chains of Met256 and Met499 at the N- and C-lobe, respectively. In the crystal structure, the cisplatin moiety bound to Met256 also interacts with Ser616 from a symmetry related molecule. Structural analyses, together with in solution data, demonstrate that the presence of iron does not affect the ability of hTF to bind cisplatin and that the cisplatin binding does not significantly alter the overall conformation of the different forms of the protein that remain able to form a complex with the transferrin receptor 1 (TfR1). These data suggest that the different hTF forms can be used as nanocarriers for targeted (combined) metallodrug delivery.

Machine learning is pivotal for predicting Peripherally Inserted Central Catheter-related venous thrombosis (PICC-RVT) risk, facilitating early diagnosis and proactive treatment. Existing models often assess PICC-RVT risk as static and discrete outcomes, which may limit their practical application.

This study aims to evaluate the effectiveness of seven diverse machine learning algorithms, including three deep learning and four traditional machine learning models, that incorporate time-series data to assess PICC-RVT risk. It also seeks to identify key predictive factors for PICC-RVT using these models.

We conducted a retrospective multi-center cohort study involving 5,272 patients who underwent PICC placement. After preprocessing patient data, the models were trained. Demographic, clinical pathology, and treatment data were analyzed to identify predictive factors. A variable analysis was then conducted to determine the most significant predictors of PICC-RVT. Model performance was evaluated using the Concordance Index (c-index) and the composite Brier score, and the Intraclass Correlation Coefficient (ICC) from cross-validation folds assessed model stability.

Deep learning models generally outperformed traditional machine learning models in terms of predictive accuracy (mean c-index: 0.949 vs. 0.732; mean integrated Brier score: 0.046 vs. 0.093). Specifically, the DeepSurv model demonstrated exceptional precision in risk assessment (c-index: 0.95). Stability varied with the number of predictive factors, with Cox-Time showing the highest ICC (0.974) with 16 predictive factors, and DeepSurv the most stable with 26 predictive factors (ICC: 0.983). Key predictors across models included albumin levels, prefill sealant type, and activated partial thromboplastin time.

Machine learning models that incorporate time-to-event data can effectively predict PICC-RVT risk. The DeepSurv model, in particular, shows excellent discriminative and calibration capabilities. Albumin levels, type of prefill sealant, and activated partial thromboplastin time are critical indicators for identifying and managing high-risk PICC-RVT patients.

Although cisplatin is widely used as a first-line chemotherapy agent, it has significant side effects. Herein, we synthesized a Pt(II) complex (Pt1) derived from o-vanillin-4-phenylthiosemicarbazone ligand and confirmed its crystal structure by x-ray crystallography. Complex Pt1 exhibited potent anticancer activity against various tested cancer cell lines, with particular efficacy against HepG-2 cells. Further investigations revealed that Pt1 inhibited the growth of HepG-2 cells through multiple mechanisms, including the generation of excessive reactive oxygen species (ROS), induction of DNA damage, enhancement of mitochondrial membrane permeability, promotion of apoptosis, and activation of autophagic cell death.

Metabolic enzymes perform moonlighting functions during tumor progression, including the modulation of chemoresistance. However, the underlying mechanisms of these functions remain elusive. Here, utilizing a metabolic clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 knockout library screen, we observe that the loss of glutamate-cysteine ligase modifier subunit (GCLM), a rate-limiting enzyme in glutathione biosynthesis, noticeably increases the sensitivity of colorectal cancer (CRC) cells to platinum-based chemotherapy. Mechanistically, we unveil a noncanonical mechanism through which nuclear GCLM competitively interacts with NF-kappa-B (NF-κB)-repressing factor (NKRF), to promote NF-κB activity and facilitate chemoresistance. In response to platinum drug treatment, GCLM is phosphorylated by P38 MAPK at T17, resulting in its recognition by importin a5 and subsequent nuclear translocation. Furthermore, elevated expression of nuclear GCLM and phospho-GCLM correlate with an unfavorable prognosis and poor benefit from standard chemotherapy. Overall, our work highlights the essential nonmetabolic role and posttranslational regulatory mechanism of GCLM in enhancing NF-κB activity and subsequent chemoresistance.

Invasive bone tumors pose a significant healthcare challenge, often requiring systemic chemotherapy and limb salvage surgery. However, these strategies are hampered by severe side effects, complex post-resection bone defects, and high local recurrence rates. To address this, we developed dual-functional bone substitute biomaterials by functionalizing commercially available bone substitute granules (Bio-Oss® and MBCP®+) with the established anticancer agent cisplatin. Physicochemical characterization revealed that Bio-Oss® granules possess a higher surface area and lower crystallinity compared to MBCP®+ granules, which enhances their capacity for cisplatin adsorption and release. In co-cultures with metastatic breast and prostate cancer cells (MDA-MB-231 and PC3) and bone marrow stromal cells (hBMSCs), cisplatin-functionalized granules and their releasates exhibited dose-dependent cytotoxic effects on cancer cells while having less impact on hBMSCs. Furthermore, investigations on the mechanism of action indicated that cisplatin induced significant cell cycle arrest and apoptosis in MDA-MB-231 and PC3 cells, contrasting with minimal effects on hBMSCs. In a rat femoral condyle defect model, cisplatin-functionalized granules did not evoke adverse effects on bone tissue ingrowth or new bone formation. Importantly, local application of cisplatin-functionalized granules resulted in negligible cisplatin accumulation without signs of apoptotic damage in kidneys and livers. Taken together, we here provide hard evidence that cisplatin-functionalized granules maintain a favorable balance between biosafety, anticancer efficacy, and bone regenerative capacity. Consequently, loading granular bone substitutes with cisplatin holds promise for local treatment of bone defects following bone tumor resections, presenting a safe and potentially more effective alternative to systemic cisplatin administration. STATEMENT OF SIGNIFICANCE: Current treatments in combating malignant bone tumors are hampered by severe side effects, high local tumor recurrence, and complex bone defects after surgery. This study explores a facile manufacturing method to render two types of commercially available bone substitute granules (Bio-Oss® and MBCP®+) suitable for local delivery of cisplatin. The use of cisplatin-functionalized granules has shown promising results both in killing cancer cells in a dose-dependent manner and in aiding bone regeneration. Importantly, this local treatment strategy avoids the systemic toxicity associated with traditional chemotherapy to excretory organs. This dual-functional strategy represents a significant advancement in bone cancer treatment, offering a safe and more efficient alternative that could improve outcomes for patients following bone tumor resection.

Platinum rechallenge is recommended for patients with small cell lung cancer (SCLC) who relapse ≥90 days after completing first-line chemotherapy, although it may not always be the most suitable option.

Articles for review were identified via PubMed and ClinicalTrials.gov searches, supplemented with non-indexed publications (e.g. conference abstracts) known to the manufacturer. We examined evidence for platinum re-exposure in patients with sensitive relapsed SCLC, and present lurbinectedin as a potential alternative. The complementary mechanisms of action of lurbinectedin and platinum, owing to opposite sensitivity of SCLC cells, may resensitize tumor cells to platinum. As efficacy outcomes with lurbinectedin are equivalent or better than those with platinum rechallenge and its hematological safety profile is more favorable, achieving maximum dose intensity is more likely. The simpler dosing schedule of lurbinectedin (1 vs 3 days) and lack of need for granulocyte colony-stimulating factor primary prophylaxis lessens treatment burden.

Incorporation of lurbinectedin into therapeutic algorithms for relapsed SCLC has challenged long-established treatment paradigms. Initial evidence indicates that using lurbinectedin after failure of first-line platinum may prolong the platinum-free interval and reserve platinum for later use. Current evidence supports lurbinectedin as a second-line option in patients with sensitive relapsed SCLC.

Postoperative radiotherapy remains the gold standard for malignant glioma treatment. Clinical limitations, including tumor growth between surgery and radiotherapy and the emergence of radioresistance, reduce treatment effectiveness and result in local disease progression. This study aimed to develop a local drug delivery system to inhibit tumor growth before radiotherapy and enhance the subsequent anticancer effects of limited-dose radiotherapy. We developed a compound of carboplatin-loaded hydrogel (CPH) incorporated with carboplatin-loaded calcium carbonate (CPCC) to enable two-stage (peritumoral and intracellular) release of carboplatin to initially inhibit tumor growth and to synergize with limited-dose radiation (10 Gy in a single fraction) to eliminate malignant glioma (ALTS1C1 cells) in a C57BL/6 mouse subcutaneous tumor model. The doses of carboplatin in CPH and CPCC treatments were 150 μL (carboplatin concentration of 5 mg/mL) and 15 mg (carboplatin concentration of 4.1 μg/mg), respectively. Mice receiving the combination of CPH-CPCC treatment and limited-dose radiation exhibited significantly reduced tumor growth volume compared to those receiving double-dose radiation alone. Furthermore, combining CPH-CPCC treatment with limited-dose radiation resulted in significantly longer progression-free survival than combining CPH treatment with limited-dose radiation. Local CPH-CPCC delivery synergized effectively with limited-dose radiation to eliminate mouse glioma, offering a promising solution for overcoming clinical limitations.

This study is dedicated to the development of multimodal anticancer agents. We have obtained ruthenium complexes conjugated with the steroid-type antitumor drug abiraterone acetate in order to take advantage of the dual antitumor properties of both ruthenium and abiraterone. The compounds exhibit good antiproliferative activity against cancer cells, with selectivity over primary fibroblasts. Real-time cell analysis revealed that compound dichlorido(η6-p-cymene)(abiraterone acetate)ruthenium(II) had pronounced antiproliferation activity compared to abiraterone acetate. Flow cytometric studies on the mechanism of cell death have revealed that the most active compound induces apoptosis more effectively than abiraterone acetate. Our findings demonstrate the potential of this novel dual-action compound as promising candidates for further development as anticancer agents.

Anti-cancer drug cisplatin (CDDP) causes severe acute kidney injury (AKI). CDDP-induced AKI does not occur immediately after administration, but rather 6 to 10 days after administration. However, the mechanism underling the delayed renal injury by CDDP is not well understood. In a previous investigation using immortalized cells derived from the S1, S2, and S3 segments of the proximal tubules, we found that S3 cells were more sensitive to CDDP than S1 and S2 cells. In this study, we examined whether S1, S2, and S3 cells would be useful in elucidating the mechanism of CDDP-induced delayed renal injury and whether the high sensitivity of S3 cells contributes to CDDP-induced delayed renal injury. Measurement of platinum (Pt) content by ICP-MS showed that Pt accumulation peaked at 15 min after CDDP exposure in each cell type. Even when the medium was replaced with CDDP-free medium after the 15-min CDDP exposure and the cells were further incubated, delayed cytotoxicity was still observed. The S3 cells exhibited greater sensitivity to CCDP than the S1 and S2 cells at all time points after the medium change. To investigate the mechanism of the CDDP-induced delayed cytotoxicity, we examined the cell cycle distribution of cells after CDDP exposure. The results showed that CDDP-induced perturbation of cell cycle was greater in S3 than in S1 and S2 cells. These results suggest that perturbation of the cell cycle in S3 cells due to enhanced CDDP-DNA adduct formation contributes to the high susceptibility of S3 cells to CDDP-induced delayed cytotoxicity.

This study investigates the impact of sub-toxic cisplatin levels on nuclear and nucleolar abnormalities and chromosome instability in HeLa cells since our current knowledge of cisplatin effects on these parameters is based on studies with high concentrations of cisplatin.

HeLa cells were exposed to gradually increasing sub-toxic doses of cisplatin (0.01 to 0.2 μg/ml). Cells treated with 0.1 and 0.2 μg/ml, termed HeLaC0.1 and HeLaC0.2, were not cisplatin-resistant, only exhibiting a slightly reduced viability, and were termed "cisplatin-sensitized cells." Giemsa and silver staining were used to detect nuclear and nucleolar abnormalities and chromosomal alterations.

Notable abnormalities were observed in HeLaC0.1 and HeLaC0.2 cells after treatment with sub-toxic concentrations of cisplatin: nuclei showed abnormal shapes, blebs, micronuclei, fragmentation, pulverization, and multinucleation; nucleoli exhibited irregular shapes and increased numbers; anaphase cells showed more nucleolar organizing regions. Abnormal chromosome segregation, heightened aneuploidy (81-140 chromosomes), polyploidy, double minutes, dicentrics, chromatid exchanges, chromatid separations, pulverization, and chromosome markers were prominently noted. These abnormalities were intensified in cells pre-sensitized to 0.02 or 0.08 μg/ml cisplatin for seven days, then exposed to 0.03 or 0.1 μg/ml cisplatin for 24 hours, and finally cultured in cisplatin-free medium for 24 hours before chromosome analysis.

HeLa cells subjected to increasing concentrations of sub-toxic cisplatin exhibited large-scale, multiple-type abnormalities in nuclei, nucleoli, chromosomes, and chromosomal numbers, indicating genetic/chromosomal instability associated with high malignancy, before the development of cisplatin resistance. These results suggest that low doses of cisplatin administration in the clinical setting may promote malignancy and caution should be used with this type of treatment.

Cisplatin is a commonly used chemotherapeutic agent in the treatment of a wide array of cancers. Due to its active transport into the kidney proximal tubule cells, cisplatin treatment can cause a buildup of this nephrotoxic compound in the kidney, resulting in acute kidney injury (AKI). About 30% of patients receiving cisplatin chemotherapy develop cisplatin-induced AKI. JP4-039 is a mitochondria-targeted reactive oxygen species (ROS) and electron scavenger. Recent studies have shown that JP4-039 mitigates a variety of genotoxic insults in preclinical studies in rodents by suppressing oxidative stress-mediated tissue damage and blocking apoptosis and ferroptosis. However, the benefits of JP4-039 treatment have not been tested in the setting of AKI. In this study, we investigated the potential renoprotective effect of JP4-039 on cisplatin-induced AKI. To address this goal, we treated mice with JP4-039 before or after cisplatin administration and analyzed them for functional and molecular changes in the kidney. JP4-039 co-administration attenuated cisplatin-induced renal dysfunction and histopathological changes. Upregulation of tubular injury markers was also suppressed by JP4-039. Mechanistically, JP4-039 suppressed lipid peroxidation, prevented tissue oxidative stress, and preserved the glutathione levels in cisplatin-injected mice. An increase in cisplatin-induced apoptosis and ferroptosis was also alleviated by the compound. Moreover, JP4-039 inhibited cytokine overproduction in cisplatin-injected mice. Together, our findings demonstrate that JP4-039 is a promising therapeutic agent against cisplatin-induced kidney injury.

Cancer is widely recognized as a serious disease that poses a significant threat to human life and health. The distinctive chemical properties and pronounced antiproliferative activity of platinum drugs are considered to be responsible for their remarkable efficacy in clinical applications. However, undesirable side effects and resistance have severely hampered the treatment of various types of cancer with platinum-based drugs. Natural products (NPs) exhibit extensive pharmacological activities and represent an important source for developing cancer therapeutics. Therefore, the combination of metals and NPs is an attractive strategy for the development of new anticancer agents. Several studies have indicated that combining metals with NPs has a synergistic enhancement effect in antitumor activity. For transition metals, there has been burgeoning research output investigating NP-conjugated platinum and gold complexes. The present article reviews the progress made over the past 5-10 years on the development of NP-conjugated platinum and gold complexes, including a brief introduction to their chemistry and mechanism of action, and a summary of their benefits.

Rhodium(III) complexes have gained attention for their anticancer potential. In this study, we investigated a rhodium(III) bipyridylsulfonamide complex (2) and its ligand (L) for their effects on breast cancer (SKBr3) and noncancerous mammary cells (HB2). Both compounds significantly reduced oxidative phosphorylation (OXPHOS) and mitochondrial function in SKBr3 cells while sparing HB2 cells. Compound 2 also increased glycolysis in both lines, suggesting a metabolic shift. Mitochondrial size and shape were altered, particularly in SKBr3 cells. Additionally, both compounds reduced cancer cell migration by disrupting actin cytoskeleton organization and the Rac1/VASP signaling pathway. These findings suggest that the rhodium(III) bipyridylsulfonamide complex selectively impairs mitochondrial dynamics and cell migration in cancer cells while sparing healthy cells, providing insight into its mechanism of action and toward its use as targeted anticancer therapy. This study lays the groundwork for future in vivo studies and further optimization of these metal-based therapeutics for clinical applications.

This work introduces a novel Pt(II) based prodrug TTFA-Platin that integrates a β-diketonate ligand TTFA with a platinum scaffold to structurally resemble carboplatin and offers intermediate kinetic lability between cisplatin and carboplatin, striking a balance between therapeutic efficacy and safety. A comprehensive stability and speciation study was conducted in various biological media, mapping the therapeutic effects of TTFA-Platin. A control molecule, TMK-Platin, was synthesized to further validate the structural-stability relationship, which displayed poor activatable features in biological systems. In vitro studies against a panel of cancer cell lines revealed that TTFA-Platin exhibited significantly higher potency compared to TMK-Platin. In vivo studies revealed that TTFA-Platin exhibited significantly lower toxicity than the reference platinum compounds. Thus, leveraging ligands that fine-tune kinetic lability and offer therapeutic benefits can help develop more effective and safer cancer treatments, addressing the limitations of existing therapies.

Accurate quantification of cisplatin (cDDP) in body fluids (blood, urine, and ascites) is crucial in monitoring therapeutic processes, assessing drug metabolism, and optimizing treatment schedules for cancer patients. Nonetheless, due to the inherent fluorescence and complexity of the body fluid matrix, along with the low cDDP concentrations in these fluids during treatment, using fluorescent sensors for fluid detection remains a subject of ongoing research. Herein, a series of water-soluble cDDP-activatable fluorescent sensors was rationally constructed by introducing thioether groups to the xanthene skeleton based on the chalcogenophilicity of platinum. These sensors exhibit excellent sensitivity and certain anti-interference capabilities for sensing cDDP in living cells, rat tissues, and zebrafish. Especially, with a simplified sample pretreatment procedure, for the first time, Rh3 and Rh4 have enabled quantitative detection of cDDP levels in diversiform body fluids from clinical ovarian and bladder cancer patients. These results are highly consistent with those obtained by ICP-MS detection. This work paves the way for utilizing fluorescent sensors in clinical body fluid analysis, thus potentially revolutionizing the monitoring methods of cDDP in clinic settings.

Cisplatin is widely employed in clinical oncology as an anticancer chemotherapy drug in clinical practice and is known for its severe ototoxic side effects. Prior research indicates that the accumulation of reactive oxygen species (ROS) plays a pivotal role in cisplatin's inner ear toxicity. Hesperidin is a flavanone glycoside extracted from citrus fruits that has anti-inflammatory and antioxidant effects. Nonetheless, the specific pharmacological actions of hesperidin in alleviating cisplatin-induced ototoxicity remain elusive. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is a critical mediator of the cellular oxidative stress response, is influenced by hesperidin. Activation of Nrf2 was shown to have a protective effect against cisplatin-induced ototoxicity. The potential of hesperidin to stimulate Nrf2 in attenuating cisplatin's adverse effects on the inner ear warrants further investigation. This study employs both in vivo and in vitro models of cisplatin ototoxicity to explore this possibility. Our results reveal that hesperidin mitigates cisplatin-induced ototoxicity by activating the Nrf2/NQO1 pathway in sensory hair cells, thereby reducing ROS accumulation, preventing hair cell apoptosis, and alleviating hearing loss.

The kidneys are the primary excretory organs for platinum drugs, making them susceptible to damage from these drugs. Cisplatin-induced acute kidney injury (CIAKI) is the most common side effect observed in patients undergoing clinical cisplatin treatment. A traditional Chinese medicinal preparation, the Yi-Qi-Jian-Pi-Xiao-Yu formula (YQJPXY), which is a modified formulation of the classical Chinese medicine formula Buyang Huanwu Decoction, has long been used in the treatment of clinical kidney diseases. It is expected to be used to ameliorate cisplatin-induced acute kidney injury. However, the mechanism of this YQJPXY for the treatment of cisplatin-induced acute kidney injury remains unclear.

The objective of this study is to examine the impact of the YQJPXY on the inhibition of ferroptosis in cisplatin-induced acute kidney injury and to elucidate the underlying mechanisms.

The active components of YQJPXY were analysed using UPLC-MS/MS. A comprehensive investigation was conducted to elucidate the effects and regulatory mechanisms of YQJPXY on CIAKI and ferroptosis in mice subjected to acute cisplatin treatment and in mice receiving cisplatin treatment after STING expression was inhibited using the STING inhibitor C176. The renoprotective effect of YQJPXY on cisplatin-treated mice was evaluated by measuring tissue damage, inflammation and pro-fibrosis. In addition, we employed network pharmacology and molecular docking methodologies to analyse the principal regulatory targets of YQJPXY. Furthermore, the expression of key proteins and markers of ferroptosis and iron metabolism, as well as the levels of key indicators related to STING-associated ferritinophagy, were examined by immunoblotting, immunohistochemistry, immunoprecipitation, quantitative real-time PCR (qPCR) and specific probes.

The results demonstrated that YQJPXY reduced the levels of indicators of injury, inflammation and pro-fibrosis in CIAKI mice, with renoprotective effects. Network pharmacological analyses revealed that ferroptosis might be the main biological process regulated by YQJPXY. Furthermore, molecular docking results indicated that STING might be a potential regulatory target of YQJPXY. Furthermore, YQJPXY treatment resulted in a significant reduction in MDA and 4-HNE levels, as well as the inhibition of ferroptosis and improvement in iron metabolic processes. Concomitantly, YQJPXY exhibited a robust protective effect on ferroptosis and iron metabolism homeostasis, as evidenced by its inhibitory action on ferritinophagy. Validation experiments utilising the cisplatin inhibitor C176 demonstrated that YQJPXY inhibits cisplatin-induced ferroptosis in kidney via STING-mediated ferritinophagy.

These suggest that YQJPXY alleviates cisplatin-induced acute kidney injury through suppressing ferroptosis via STING-NCOA4-mediated Ferritinophagy.

Chemotherapy resistance is the main reason of treatment failure in gastric cancer (GC). However, the mechanism of oxaliplatin (OXA) resistance remains unclear. Here, we demonstrate that extracellular mechanical signaling plays crucial roles in OXA resistance within GC. We selected OXA-resistant GC patients and analyzed tumor tissues by single-cell sequencing, and found that the mitochondrial content of GC cells increased in a biosynthesis-independent manner. Moreover, we found that the increased mitochondria of GC cells were mainly derived from mesenchymal stromal cells (MSCs), which could repair the mitochondrial function and reduce the levels of mitophagy in GC cells, thus leading to OXA resistance. Furthermore, we investigated the underlying mechanism and found that mitochondrial transfer was mediated by mechanical signals of the extracellular matrix (ECM). After OXA administration, GC cells actively secreted ECM in the tumor microenvironment (TEM), increasing matrix stiffness of the tumor tissues, which promoted mitochondria to transfer from MSCs to GC cells via microvesicles (MVs). Meanwhile, inhibiting the mechanical-related RhoA/ROCK1 pathway could alleviate OXA resistance in GC cells. In summary, these results indicate that matrix stiffness could be used as an indicator to identify chemotherapy resistance, and targeting mechanical-related pathway could effectively alleviate OXA resistance and improve therapeutic efficacy.

The current investigations aimed to investigate the potential synergistic effect of Roflumilast (ROF) and Selenium nanoparticles (SeNPs) administration on Cisplatin (Cis) -induced nephrotoxicity.

Fifty male rats were divided into five groups; Control group: animals were administered 0.9 % saline solution. Cis group: animals were injected with a single dose of 6 mg/kg. ROF group: Rats received a dosage of 1.2 mg/kg orally daily for 11 days. SeNPs group: animals orally received 0.5 mg/kg of ROF daily for 11 days. The ROF + SeNPs group was administered both after receiving a Cis injection for 11 days. Animals were sacrificed at 5 and 11 days, and the urine and blood samples were collected on day 5 and day 11 for chemical analysis, while kidney samples were obtained for molecular, histological, and immunohistochemical studies.

The levels of serum creatinine, Blood urea nitrogen (BUN), and total protein were elevated in the Cis group compared to the control group (p < 0.05). While the combination of ROF and SeNPs dramatically decreased these values after 5 and 11 days (p < 0.05). In addition, Cis caused renal oxidative stress by elevating MDA levels and suppressing the activities of SOD, GSH, and CAT. Similarly, these effects were modulated by ROF and SeNPs after 11 days (p < 0.05). Furthermore, the concurrent administration of ROF and SeNPs resulted in a significant increase in the expression of HO-1, Nrf2, and Bcl2, while decreasing the expression of BAX and IL-6 compared to the Cis group after 11 days (P < 0.05).

The study showed that both ROF and SeNPs had significant therapeutic potential in reducing the pathological alterations caused by Cis.

In this study, we investigated the potential role of PrxI in cis-diamminedichloroplatinum (cisplatin)-induced renal damage in mice. The anticancer drug cisplatin is a chemotherapeutic agent that is widely used to treat solid tumors. Cisplatin-induced nephrotoxicity is a serious dose-limiting side effect, primarily caused by oxidative stress. The oxidative stress further damages DNA, membranes, and mitochondria, and increases endoplasmic reticulum (ER) stress. Cisplatin produces reactive oxygen species (ROS) through Cytochrome P450 2E1 (CYP2E1) and localizes to the surface of the ER, where CYP2E1 is located. Among the six Prx isoforms, Prx I was selectively degraded in cisplatin-treated kidneys during severe renal function damage. Prx I degradation is blocked in mouse proximal tubular cells treated with 3-methyladenine, an autophagy inhibitor, and in MEF lacking ATG7. Moreover, increased ROS levels on the ER surface due to CYP2E1 overexpression further accelerated Prx I degradation. These results suggest that Prx I degradation is largely mediated through autophagy, which is promoted by cisplatin-induced ER stress. Ablation of Prx I exacerbated cisplatin-induced nephrotoxicity and significantly increased the abundance of oxidative stress, ER stress, and inflammatory markers in the kidney, indicating that Prx I plays a protective role against cisplatin-induced nephrotoxicity.