Search Results (105)

Porcine teschovirus (PTV) circulates in pig populations, causing clinical diseases such as poliomyelitis, reproductive disorders, and pneumonia. However, the molecular mechanisms underlying the pathogenesis of PTV infection have not been fully elucidated. Here, we found that PTV infection does not activate the promoters of NF-κB or IFN-β. The expression of PTV 3C^pro inhibits the promoter activity of NF-κB and IFN-β stimulated by SeV and inhibits the downstream transcription of NF-κB and IFN-β by blocking the phosphorylation and nuclear translocation of NF-κB. Coimmunoprecipiation (co-IP) experiments demonstrated that 3C^pro and NF-κB interact. The degradation of NF-κB was unaffected by inhibitors targeting lysosomes (NH4Cl), proteasomes (MG132), or caspases (Z-VAD-FMK). The protease activity of 3C^pro, which relies on its catalytic active site, is vital for NF-κB cleavage and degradation. Loss of proteolytic activity in mutants abolished NF-κB degradation, impairing the ability of 3C^pro to suppress SeV-induced innate immunity and restore VSV-GFP replication, thereby underscoring its critical role in immune evasion by targeting NF-κB. This study reveals novel mechanisms underlying PTV-mediated suppression of host innate immunity. Full article

Acute erythroid leukemia (AEL) is a rare and aggressive hematological malignancy managed with chemotherapy, targeted therapies, and stem cell transplantation. However, these treatments often suffer from limitations such as refractoriness, high toxicity, recurrence, and drug resistance, underscoring the urgent need for novel therapeutic approaches. Dibromo-edaravone (D-EDA) is a synthetic derivative of edaravone (EDA) with unreported anti-leukemic properties. In this study, D-EDA demonstrated potent cytotoxicity against HEL cells with an IC₅₀ value of 8.17 ± 0.43 μM using an MTT assay. Morphological analysis via inverted microscopy revealed reductions in cell number and signs of cellular crumpling and fragmentation. Flow cytometry analysis, Hoechst 33258 staining, Giemsa staining, a JC-1 assay, and a reactive oxygen species (ROS) assay showed that D-EDA induced apoptosis in HEL cells. Furthermore, D-EDA induced S-phase cell cycle arrest. Western blot analysis showed significant upregulation of key apoptosis-related proteins, including cleaved caspase-9, cleaved caspase-3, and cleaved poly ADP-ribose polymerase (PARP), alongside a reduction in Bcl-2 expression. Additionally, oncogenic markers such as c-Myc, CyclinA2, and CDK2 were downregulated, while the cell cycle inhibitor p21 was upregulated. Mechanistic studies involving molecular docking, a cellular thermal shift assay (CETSA), the caspase inhibitor Z-VAD-FMK, JAK2 inhibitor Ruxolitinib, and STAT3 inhibitor Stattic revealed that D-EDA activates the caspase cascade and inhibits the JAK2-STAT3 signaling pathway in HEL cells. In vivo, D-EDA improved spleen structure, increased the hemolysis ratio, and extended survival in a mouse model of acute erythroleukemia. In conclusion, D-EDA induces apoptosis via the caspase cascade and JAK2-STAT3 signaling pathway, demonstrating significant anti-leukemia effects in vitro and in vivo. Thus, D-EDA may be developed as a potential therapeutic agent for acute erythroleukemia. Full article

Infectious bronchitis virus (IBV) poses a major challenge to poultry health and productivity. This study examined how inflammatory cell death pathways influence the replication and pathogenesis of two IBV strains—respiratory Connecticut (Conn) A5968 and nephropathogenic Delmarva (DMV)/1639—in chicken macrophages. Low serum conditions enhanced viral replication, reduced cell viability, and promoted apoptosis and necroptosis, with DMV/1639 showing more pronounced effects. Modulation of the cyclooxygenase-2/prostaglandin E2 (COX-2/PGE2) pathway displayed strain-specific effects, mitigating necroptosis in DMV/1639-infected cells but exacerbating apoptosis and necroptosis in Conn A5968-infected cells. Broad caspase inhibition (z-VAD-FMK) reduced necroptosis, while selective caspase-1/4 inhibition heightened apoptotic responses. Caspase-8 inhibition selectively reduced necroptosis in DMV/1639 infections but increased apoptosis and necroptosis in Conn A5968 infections. NLRP3 inflammasome and RIPK1 inhibition decreased cell viability and increased apoptosis in both strains but had distinct effects on necroptosis. These findings reveal the strain-specific regulation of viral replication, apoptosis, and necroptosis, underscoring the intricate interplay between IBV and host inflammatory pathways. Understanding these mechanisms provides novel insights into IBV pathogenesis and highlights potential therapeutic strategies to mitigate its impact on poultry health. Full article

Licochalcone A (LicoA) possesses anti-tumor properties. However, the potential therapeutic effect of LicoA on uterine leiomyomas (ULs) remains unknown. In this study, the effects of LicoA on the proliferation of ULs and its underlying mechanism were explored. LicoA treatment significantly decreased the viability of uterine smooth muscle cells (UtSMCs) and ELT3 cells in a dose-dependent manner. The induction of ELT3 cell apoptosis by LicoA was accompanied by the increased generation of reactive oxygen species (ROS), elevated endoplasmic reticulum (ER) stress (GRP78/IRE1α/ATF6/CHOP), and the increased expression of proapoptotic proteins (c-caspase-3, c-caspase-9, and c-PARP). The ability of Z-VAD-FMK (a caspase inhibitor) and n-acetylcysteine (NAC; a cell membrane permeable antioxidant) to reverse LicoA-induced ROS-mediated ER stress pathways also observed. Furthermore, GRP78 or JNK knockdown was involved in LicoA-induced ROS-mediated ER stress and apoptosis in ELT3 cells. In immunodeficient mice, LicoA significantly suppressed the growth of ELT3 tumor cells, without toxicity. This study is the first to show that LicoA exerts anti-leiomyoma effects via the modulation of ROS-mediated ER stress-induced apoptosis through the JNK/GRP78/NRF2 signaling pathway. Full article

Bladder cancer is a globally prevalent urological malignancy, with transitional carcinoma (TCC) representing the majority of cases. Cisplatin is the primary drug for metastatic bladder cancer chemotherapy; however, its application is limited by nephrotoxicity and resistance. Signal Transducer and Activator of Transcription 3 (STAT3) is an oncogenic transcription factor often overactivated in various cancers, making it an appealing drug target. Fucoxanthin, a marine carotenoid, has significant anticancer properties. This study explored Fucoxanthin’s cytotoxic effects and its potential to potentiate the efficacy of Cisplatin, along with the mechanisms underlying these effects, on human bladder TCC cells. We demonstrated that Fucoxanthin is cytotoxic to bladder TCC cells by inducing apoptosis, evidenced by z-VAD-fmk-mediated annulment of Fucoxanthin’s cytotoxicity. Furthermore, Fucoxanthin reduced the levels of inherent or interleukin-6-induced tyrosine 705-phosphorylated STAT3 accompanied by downregulating BCL-xL, a well-established STAT3 target. Notably, ectopic expression of STAT3-C, a dominant-active STAT3 mutant, or BCL-xL thwarted Fucoxanthin’s proapoptotic and cytotoxic actions. Moreover, Fucoxanthin at subtoxic dosages enhanced the susceptibility to Cisplatin-induced apoptosis of bladder TCC cells initially resistant to Cisplatin. Remarkably, this Cisplatin-sensitizing effect of Fucoxanthin was abrogated when cells ectopically expressed STAT3-C or BCL-xL. Overall, for the first time, we proved that the proapoptotic, cytotoxic, and Cisplatin-sensitizing effects of Fucoxanthin on human bladder TCC cells are attributed to the blockade of the STAT3/BCL-xL axis. Our findings highlight that targeting the STAT3/BCL-xL axis is a promising strategy to eliminate bladder TCC cells and facilitate Cisplatin sensitization, and further support the potential of incorporating Fucoxanthin into Cisplatin-based chemotherapy for treating bladder cancer. Full article

Radiotherapy is a powerful tumor therapeutic strategy for gastric cancer patients. However, radioresistance is a major obstacle to kill cancer cells. Ginger (Zingiber officinale Roscoe) exerts a potential function in various cancers and is a noble combined therapy to overcome radioresistance in gastric cancer radiotherapy. In this study, we suggested that 8-shogaol, a monomethoxybenzene compound extracted from Zingiber officinale Roscoe, has an anti-cancer and anti-inflammatory activity. In lipopolysaccharide (LPS)-induced inflammatory murine models in vivo and in vitro, 8-shogaol suppressed LPS-mediated cytokine production, including COX-2, TNFα, IL-6, and IL-1β. In xenograft mouse models of AGS gastric cancer cell lines, 8-shogaol reduced tumor volume. In gastric cancer cell lines AGS and NCI-N87, 8-shogaol reduced cell viability and increased caspase-3 activity and cytotoxicity LDH. However, combined with Z-VAD-FMK, 8-shogaol blocked caspase-dependent apoptotic cell death. 8-Shogaol induced intracellular reactive oxygen species (ROS) production, intracellular calcium (Ca²⁺) release, and endoplasmic reticulum (ER) stress response via the PERK-CHOP signaling pathway. Thapsigargin (TG), an ER stressor, mediated synergistic apoptosis and cell death in 8-shogaol-treated AGS and NCI-N87 cell lines. Nevertheless, loss of PERK or CHOP function suppressed ER-stress-induced apoptosis and cell death in 8-shogaol-treated AGS and NCI-N87 cell lines. 8-Shogaol-induced NADPH oxidase 4 (NOX4) activation is related to ROS generation. However, NOX4 knockdown and ROS inhibitors DPI or NAC blocked ER-stress-induced apoptosis by suppressing the inhibition of cell viability and the enhance of caspase-3 activity, intracellular ROS activity, and cytotoxicity LDH in 8-shogaol-treated AGS and NCI-N87 cell lines. Radioresistant gastric cancer models (AGSR and NCI-N87R) were developed and combined with 8-shogaol and radiation (2 Gy) to overcome radioresistance via the upregulation of N-cadherin and vimentin and the downregulation of E-cadherin. Therefore, these results indicated that 8-shogaol is a novel combined therapeutic strategy in gastric cancer radiotherapy. Full article

The extract of the rhizome of Cnidium officinale Makino has potential anti-cancer and anti-inflammatory effects in many diseases, such as cancer. However, the biological functions of falcarindiol (FAD) in breast cancer are not fully understood. This study proved the anti-inflammatory and anti-cancer effects of FAD in breast cancer. Breast cancer models confirmed that FAD reduces cell viability and decreases the tumor volume of xenograft mouse models in a dose-dependent manner. FAD mediated caspase-3-dependent apoptosis in MDA-MB-231 and MCF-7 cells, whereas Z-VAD-FMK in combination with FAD inhibited caspase-3-induced apoptosis. FAD mediates apoptosis through cytosolic reactive oxygen species (ROS) and calcium (Ca²⁺) production and ER stress signaling pathways. In addition, FAD combined with thapsigargin (TG) exerts a synergistic apoptotic cell death effect. In the loss-of-function experiments, PERK or CHOP ablation suppressed intracellular ROS and Ca²⁺ release and ER stress-induced apoptosis in FAD-treated breast cancer models. Since there is a relationship between ROS and NADPH Oxidase 4 (NOX4), Nox4 ablation blocked ER stress-mediated apoptotic cell death by inhibiting ROS release in FAD-induced breast cancer models. Radioresistant models, such as MCF-7R and MDA-MB-231R, were developed to address the cellular radioresistance in clinical radiotherapy. FAD combined with radiation (2 Gy) overcame radioresistance via the inhibition of the epithelial–mesenchymal transition (EMT) phenomenon, such as the upregulation of PPARγ, VIM, and CDH2 and the downregulation of CDH1. Consequently, these results show that FAD may be a novel treatment as a breast cancer therapy. Full article

Background/Objectives: Peroxisome proliferator–activated receptor γ (PPARγ) plays a key role in mediating anti-inflammatory and anticancer effects in the tumor microenvironment. Kaurenoic acid (KA), a diterpene compound isolated from Sphagneticola trilobata (L.) Pruski, has been demonstrated to exert anti-inflammatory, anticancer, and antihuman immunodeficiency virus effects. Methods: In this study, we identified KA as a novel activator of PPARγ with potent anti-inflammatory and antitumor effects both in vitro and in vivo. Given the potential of PPARγ regulators in overcoming radioresistance and chemoresistance in cancer therapies, we hypothesized that KA may enhance the efficacy of breast cancer radiotherapy. Results: In a lipopolysaccharide (LPS)-induced mouse inflammation model, KA treatment reduced the levels of pro-inflammatory cytokines, including COX-2, IL-6, IL-1β, and TNFα. In a xenograft mouse mode of breast cancer, KA treatment inhibited tumor growth. Specifically, KA treatment enhanced caspase-3 activity and cytotoxicity against MDA-MB-231 and MCF-7 breast cancer cells. When KA was co-treated with a caspase inhibitor, Z-VAD-FMK, caspase-dependent apoptosis was suppressed in these cells. KA was found to induce the generation of cytosolic calcium ions (Ca²⁺) and reactive oxygen species (ROS), triggering endoplasmic reticulum (ER) stress via the PERK-ATF4-CHOP axis. Hence, the ER stressor thapsigargin (TG) synergized with KA treatment to enhance apoptosis in these cells, while the loss of the PERK or CHOP function inhibited this phenomenon. KA treatment was shown to induce oxidative stress via the NADPH oxidase 4 (NOX4) and stimulate ROS production. Specifically, NOX4 knockdown (KD) and antioxidant treatment (N-acetyl cysteine or diphenyleneiodonium) suppressed such ER stress–mediated apoptosis by inhibiting KA-enhanced caspase-3 activity, cytotoxicity, and intracellular ROS production in the treated cells. In radioresistant MDA-MB-231R and MCF-7R cells, KA combined with 2 Gy radiation overcame radioresistance by upregulating PPARγ and modulating epithelial–mesenchymal transition (EMT) markers, such as E-cadherin, N-cadherin, and vimentin. In PPARγ KD MDA-MB-231R and MCF-7R cells, this phenomenon was inhibited due to reduced PPARγ and NOX4 expression. Conclusions: In conclusion, these findings demonstrated KA as a novel PPARγ regulator with promising potential to enhance the efficacy of breast cancer radiotherapy. Full article

Radiotherapy combined with a radiosensitizer represents an important treatment for head and neck squamous cell carcinoma (HNSCC). Only a few chemotherapy agents are currently approved as radiosensitizers for targeted therapy. Oral squamous cell carcinoma is one of the deadliest cancers, with approximately ~500,000 new diagnosed cases and 145,000 deaths worldwide per year. The incidence of new cases continues to increase in developing countries. This study aimed to investigate the effect of Croton tonkinensis and Curcuma longa on cell viability in OSCC cells. The HNSCC cell line OML1 and its radiation-resistant clone OML1-R were used. The anticancer effect and the mechanism of action of Croton tonkinensis and Curcuma longa in OSCC cells were analyzed by using cell viability assays, Western blot analysis, and Tranwell migration assays. The results showed that Croton tonkinensis concentration-dependently reduced the viability of OML1 and OML1-R (radioresistant) cells by downregulating the levels of AKT/mTOR mediators, such as p110α, p85, pAKT (ser473), p-mTOR (ser2448), and p-S6 Ribosomal (ser235/236). We found that cotreatment of OML1 and OML1R cells with either zVAD-FMK (apoptosis inhibitor), Ferrostatin-1 (Fer-1, a ferroptosis inhibitor), or chloroquine (CQ, an autophagy inhibitor) markedly reduced cell death. These results demonstrate that Croton tonkinensis exhibits anti-proliferation activity and highlight the therapeutic potential of small-molecule inhibitors against PI3K/mTOR signaling for radiosensitization in HNC treatment. Full article

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising chemotherapeutic agent because of its selective apoptotic action on cancer cells. However, resistance to TRAIL-induced apoptosis remains a challenge in many cancers. The gintonin-enriched Panax ginseng extract fraction (GEF) has diverse pharmacological benefits. We explored the combined efficacy of GEF and TRAIL in inducing apoptosis in human renal cell carcinoma (RCC) cells. The effect of GEF treatment on the viability, clonogenic potential, wound healing, and TRAIL-induced apoptotic signaling of RCC cells was studied in vitro. Our investigation revealed that GEF pre-treatment sensitized RCC cells to TRAIL-induced apoptosis, as evidenced by DNA fragmentation and cell proliferation, colony formation, and migration inhibition. This sensitization was linked to the upregulation of death receptors 4 and 5 and alterations in apoptotic protein expression, notably, the decreased expression of the Mu-2-related death-inducing gene, a novel anti-apoptotic protein. Our findings underscore the necessity of caspase activation for GEF/TRAIL-induced apoptosis using the pan-caspase inhibitor Z-VAD-FMK. This study demonstrates that GEF sensitizes human RCC cells to TRAIL-induced apoptosis by upregulating DR4/5 and modulating apoptotic protein expression. These findings suggest a promising strategy for overcoming TRAIL resistance in cancer therapy and highlight the potential of GEF as a valuable adjunct to TRAIL-based treatments. Full article

Cancer has become a consistent concern globally and increasingly fatal. Malignant melanoma is a rising concern, with its increased mortality. Kaempferia parviflora Wall. ex Baker (K. parviflora (KP)), commonly known as black ginger, is well known for its medicinal contributions. For the first time, in the following study we investigated the antimelanoma potential of Laos KP extracts in human cell lines. KP extracts (KPE) in methanol, DCM, and ethyl acetate showed strong cell inhibition in both melanomas, with KPE-DCM being particularly effective in inhibiting melanoma cell migration, invasion, and proliferation by inducing cell cycle arrest and apoptosis, while KPE-Hexane exhibited a low cell inhibition rate and a more limited effect. KPE affected the increased expression of caspase-3, PARP andBax and the decreased expression of the BcL-2, Mu-2-related death-inducing gene (MUDENG, MuD) protein. Furthermore, KPE enhanced apoptotic cells in the absence and presence of the pancaspase inhibitor Z-VAD-FMK. Interestingly, these apoptotic cells were significantly suppressed by the caspase inhibitor. Moreover, elevated mitochondrial membrane potential (MMP) and intracellular reactive oxygen species (ROS) levels, suggestive of KPE’s mitochondrial-mediated apoptosis in melanoma cells, were also confirmed. KPE treatment increased MMP levels, and upregulated the generation of ROS in A375 cells but not in A2058 cells. However, pretreatment with an ROS scavenger (NAC) suppressed KPE-induced cell death and ROS generation. These results clearly pointed out KPE-induced mitochondrial-mediated apoptotic cell death as the mechanism behind the inhibition of the human melanoma cells. Future studies exploring the role of specific ROS sources and their interaction with mitochondrial dynamics could deepen the existing understanding on KPE-induced apoptosis. Full article

Apoptosis induction with taxanes or anthracyclines is the primary therapy for TNBC. Cancer cells can develop resistance to anticancer drugs, causing them to recur and metastasize. Therefore, non-apoptotic cell death inducers could be a potential treatment to circumvent apoptotic drug resistance. In this study, we discovered two novel compounds, TPH104c and TPH104m, which induced non-apoptotic cell death in TNBC cells. These lead compounds were 15- to 30-fold more selective in TNBC cell lines and significantly decreased the proliferation of TNBC cells compared to that of normal mammary epithelial cell lines. TPH104c and TPH104m induced a unique type of non-apoptotic cell death, characterized by the absence of cellular shrinkage and the absence of nuclear fragmentation and apoptotic blebs. Although TPH104c and TPH104m induced the loss of the mitochondrial membrane potential, TPH104c- and TPH104m-induced cell death did not increase the levels of cytochrome c and intracellular reactive oxygen species (ROS) and caspase activation, and cell death was not rescued by incubating cells with the pan-caspase inhibitor, carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone (Z-VAD-FMK). Furthermore, TPH104c and TPH104m significantly downregulated the expression of the mitochondrial fission protein, DRP1, and their levels determined their cytotoxic efficacy. Overall, TPH104c and TPH104m induced non-apoptotic cell death, and further determination of their cell death mechanisms will aid in the development of new potent and efficacious anticancer drugs to treat TNBC. Full article

Background: Hepatocellular carcinoma (HCC), currently ranking as the third most lethal malignancy, poses a grave threat to human health. Ferroptosis, a form of programmed cell demise, has emerged as a promising therapeutic target in HCC treatment. In this study, we investigated the impact of ginsenoside RK1 on ferroptosis induction in HCC cells and elucidated the underlying mechanisms. Methods: The HCC cell line HepG2 was utilized to evaluate the effects of ginsenoside RK1. Distinct dosages of ginsenoside RK1 (25 μM, 50 μM, and 100 μM) were selected based on half-maximal inhibitory concentration (IC50) values. Cellular viability was assessed using a CCK8 assay, cytotoxicity was measured via lactate dehydrogenase (LDH) release assay, and colony-forming ability was evaluated using the clone formation assay. Various inhibitors targeting apoptosis (Z-VAD-FMK 20 μM), necrosis (Nec-1, 10 μM), and ferroptosis (Fer-1, 10 μM; Lip-1, 1 μM) were employed to assess ginsenoside RK1’s impact on cell demise. Intracellular levels of key ions, including glutathione (GSH), malondialdehyde (MDA), and iron ions, were quantified, and the protein expression levels of ferroptosis-related genes were evaluated. The sensitivity of HCC cells to ferroptosis induction by ginsenoside RK1 was examined following the overexpression and silencing of the aforementioned target genes. Results: Ginsenoside RK1 exhibited an inhibitory effect on HCC cells with an IC50 value of approximately 20 μM. It attenuated cellular viability and colony-forming capacity in a dose-dependent manner, concurrently reducing intracellular GSH levels and increasing intracellular Malondialdehyde (MDA) and iron ion contents. Importantly, cell demise induced by ginsenoside RK1 was specifically counteracted by ferroptosis inhibitors. Furthermore, the modulation of Ferroptosis suppressor protein 1 (FSP1) expression influenced the ability of ginsenoside RK1 to induce ferroptosis. FSP1 overexpression or silencing enhanced or inhibited ferroptosis induction by ginsenoside RK1, respectively. Conclusions: Ginsenoside RK1 enhances ferroptosis in hepatocellular carcinoma through an FSP1-dependent pathway. Full article

Ferroptosis hallmarked by lipid peroxidation and iron homeostasis imbalance is involved in the occurrence and development of various diseases. The plant growth regulator chlormequat chloride (CCC) can contribute to the causality and exacerbation of reproductive disorders. However, the mechanism by which CCC may cause Leydig cell attenuation remains poorly understood. In this study, TM3 Leydig cells were used to investigate the inhibitory effect of CCC on cell growth and its possible mechanism. The results showed that CCC caused apoptosis, pyroptosis, ferroptosis and necroinflammation in TM3 cells. By comparing the effects of ferroptosis inhibitor Ferrostatin-1 (Fer-1) and pan-Caspase inhibitor Z-VAD-FMK (ZVF) on lipid peroxidation and Caspase-mediated regulated cell death (RCD), we found that Fer-1 was better at rescuing the growth of TM3 cells than ZVF. Although ZVF reduced mitochondrial ROS level and inhibited the activation of Caspase3 and Caspase1, it could not significantly ameliorate lipid peroxidation and the levels of IL-1β and HMGB1 like Fer-1. Therefore, ferroptosis might be a key non apoptotic RCD mode responsible for CCC-driven inflammation, leading to weakened viability and proliferation of TM3 cells. In addition, overexpression of ferritin light chain (FTL) promoted the resistance of TM3 cells to CCC-induced ferroptosis-mediated inflammation and to some extent improved the inhibition of viability and proliferation. Altogether, ferroptosis-initiated inflammation might play a key role in CCC-impaired TM3 cell growth. Full article

Cisplatin is a widely used anti-cancer drug for treating solid tumors, but it is associated with severe side effects, including nephrotoxicity. Various studies have suggested that the nephrotoxicity of cisplatin could be overcome; nonetheless, an effective adjuvant drug has not yet been established. Oleanolic acid acetate (OAA), a triterpenoid isolated from Vigna angularis, is commonly used to treat inflammatory and allergic diseases. This study aimed to investigate the protective effects of OAA against cisplatin-induced apoptosis and necroptosis using TCMK-1 cells and a mouse model. In cisplatin-treated TCMK-1 cells, OAA treatment significantly reduced Bax and cleaved-caspase3 expression, whereas it increased Bcl-2 expression. Moreover, in a cisplatin-induced kidney injury mouse model, OAA treatment alleviated weight loss in the body and major organs and also relieved cisplatin-induced nephrotoxicity symptoms. RNA sequencing analysis of kidney tissues identified lipocalin-2 as the most upregulated gene by cisplatin. Additionally, necroptosis-related genes such as receptor-interacting protein kinase (RIPK) and mixed lineage kinase domain-like (MLKL) were identified. In an in vitro study, the phosphorylation of RIPKs and MLKL was reduced by OAA pretreatment in both cisplatin-treated cells and cells boosted via co-treatment with z-VAD-FMK. In conclusion, OAA could protect the kidney from cisplatin-induced nephrotoxicity and may serve as an anti-cancer adjuvant. Full article