Selenium in plants: A nexus of growth, antioxidants, and phytohormones.

Selenium (Se) is an essential micronutrient for both human and animals. Plants serve as the primary source of Se in the food chain. Se concentration and availability in plants is influenced by soil properties and environmental conditions. Optimal Se levels promote plant growth and enhance stress tolerance, while excessive Se concentration can result in toxicity. Se enhances plants ROS scavenging ability by promoting antioxidant compound synthesis. The ability of Se to maintain redox balance depends upon ROS compounds, stress conditions and Se application rate. Furthermore, Se-dependent antioxidant compound synthesis is critically reliant on plant macro and micro nutritional status. As these nutrients are fundamental for different co-factors and amino acid synthesis. Additionally, phytohormones also interact with Se to promote plant growth. Hence, utilization of phytohormones and modified crop nutrition can improve Se-dependent crop growth and plant stress tolerance. This review aims to explore the assimilation of Se into plant proteins, its intricate effect on plant redox status, and the specific interactions between Se and phytohormones. Furthermore, we highlight the proposed physiological and genetic mechanisms underlying Se-mediated phytohormone-dependent plant growth modulation and identified research opportunities that could contribute to sustainable agricultural production in the future.

Discovery of lupus nephritis targeted inhibitors based on De novo molecular design: comprehensive application of vinardo scoring, ADMET analysis, and molecular dynamics simulation.

Lupus Nephritis (LN) is an autoimmune disease affecting the kidneys, and conventional drug studies have limitations due to its imprecise and complex pathogenesis. Therefore, the aim of this study was to design a novel Lupus Nephritis-targeted drug with good clinical due potential, high potency and selectivity by computer-assisted approach.NIK belongs to the serine/threonine protein kinase, which is gaining attention as a drug target for Lupus Nephritis. we used bioinformatics, homology modelling and sequence comparison analysis, small molecule ab initio design, ADMET analysis, molecular docking, molecular dynamics simulation, and MM/PBSA analysis to design and explore the selectivity and efficiency of a novel Lupus Nephritis-targeting drug, ClImYnib, and a classical NIK inhibitor, NIK SMI1. We used bioinformatics techniques to determine the correlation between lupus nephritis and the NF-κB signaling pathway. De novo drugs design was used to create a NIK-targeted inhibitor, ClImYnib, with lower toxicity, after which we used molecular dynamics to simulate NIK SMI1 against ClImYnib, and the simulation results showed that ClImYnib had better selectivity and efficiency. Our research delves into the molecular mechanism of protein ligands, and we have designed and validated an excellent NIK inhibitor using multiple computational simulation methods. More importantly, it provides an idea of target designing small molecules.Communicated by Ramaswamy H. Sarma.

Development and experimental verification of a prognosis model for disulfidptosis-associated genes in HNSCC.

Disulfidptosis is a newly discovered cell death pattern that has been less studied in head and neck squamous carcinoma (HNSCC). Exploring the molecular features of different subtypes of HNSCC based on disulfidptosis-associated genes (DAGs) is important for HNSCC. In addition, immunotherapy plays a pivotal role in the treatment of HNSCC. Exploring the sensitivity of immunotherapies and developing predictive models is essential for HNSCC. We analyzed the expression and mutational status of DAGs in 790 HNSCC patients and correlated the dates with clinical prognosis. HNSCC patients were divided into 2 groups based on their DAG expression. The relationship between DAGs, risk genes, and the immune microenvironment was analyzed using the CIBERSORT algorithm. A disulfidptosis risk model was constructed based on 5 risk genes using the LASSO COX method. To facilitate the clinical applicability of the proposed risk model, we constructed column line plots and performed stem cell correlation analysis and antitumor drug sensitivity analysis. Two different disulfidptosis-associated clusters were identified using consistent unsupervised clustering analysis. Correlations between multilayer DAG alterations and clinical characteristics and prognosis were observed. Then, a well-performing disulfidptosis-associated risk model (DAG score) was developed to predict the prognosis of HNSCC patients. We divided patients into high-risk and low-risk groups based on the DAG score and found that patients in the low-risk group were more likely to survive than those in the high-risk group (P < .05). A high DAG score implies higher immune cell infiltration and increased mutational burden. Also, univariate and multivariate Cox regression analyses revealed that the DAG score was an independent prognostic predictor for patients with HNSCC. Subsequently, a highly accurate predictive model was developed to facilitate the clinical application of DAG scores, showing good predictive and calibration power. Overall, we present a comprehensive overview of the DAG profile in HNSCC and develop a new risk model for the therapeutic status and prognosis of patients with HNSCC. Our findings highlight the potential clinical significance of DAG and suggest that disulfidptosis may be a potential therapeutic target for patients with HNSCC.

Dihydroartemisinin, a potential PTGS1 inhibitor, potentiated cisplatin-induced cell death in non-small cell lung cancer through activating ROS-mediated multiple signaling pathways.

Dihydroartemisinin (DHA) exerts an anti-tumor effect in multiple cancers, however, the molecular mechanism of DHA and whether DHA facilitates the anti-tumor efficacy of cisplatin in non-small cell lung cancer (NSCLC) are unclear. Here, we found that DHA potentiated the anti-tumor effects of cisplatin in NSCLC cells by stimulating reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress, C-Jun-amino-terminal kinase (JNK) and p38 MAPK signaling pathways both in vitro and in vivo. Of note, we demonstrated for the first time that DHA inhibits prostaglandin G/H synthase 1 (PTGS1) expression, resulting in enhanced ROS production. Importantly, silencing PTGS1 sensitized DHA-induced cell death by increasing ROS production and activating ER-stress, JNK and p38 MAPK signaling pathways. In summary, our findings provided new experimental basis and therapeutic prospect for the combined therapy with DHA and cisplatin in some NSCLC patients.

Dibutyl phthalate exposure induced mitochondria-dependent ferroptosis by enhancing VDAC2 in zebrafish ZF4 cells.

Dibutyl phthalate (DBP) contamination has raised global concern for decades, while its health risk with toxic mechanisms requires further elaboration. This study used zebrafish ZF4 cells to investigate the toxicity of ferroptosis with underlying mechanisms in response to DBP exposure. Results showed that DBP induced ferroptosis, characterized by accumulation of ferrous iron, lipid peroxidation, and decrease of glutathione peroxidase 4 levels in a time-dependent manner, subsequently reduced cell viability. Transcriptome analysis revealed that voltage-dependent anion-selective channel (VDAC) in mitochondrial outer membrane was upregulated in ferroptosis signaling pathways. Protecting mitochondria with a VDAC2 inhibitor or siRNAs attenuated the accumulation of mitochondrial superoxide and lipid peroxides, the opening of mitochondrial permeability transition pore (mPTP), and the overload of iron levels, suggesting VDAC2 oligomerization mediated the influx of iron into mitochondria that is predominant and responsible for mitochondria-dependent ferroptosis under DBP exposure. Furthermore, the pivotal role of activating transcription factor 4 (ATF4) was identified in the transcriptional regulation of vdac2 by ChIP assay. And the intervention of atf4b inhibited DBP-induced VDAC2 upregulation and oligomerization. Taken together, this study reveals that ATF4-VDAC2 signaling pathway is involved in the DBP-induced ferroptosis in zebrafish ZF4 cells, contributing to the in-depth understanding of biotoxicity and the ecological risk assessment of phthalates.

Tolerogenic Nano-/Microparticle Vaccines for Immunotherapy.

Autoimmune diseases, allergies, transplant rejections, generation of antidrug antibodies, and chronic inflammatory diseases have impacted a large group of people across the globe. Conventional treatments and therapies often use systemic or broad immunosuppression with serious efficacy and safety issues. Tolerogenic vaccines represent a concept that has been extended from their traditional immune-modulating function to induction of antigen-specific tolerance through the generation of regulatory T cells. Without impairing immune homeostasis, tolerogenic vaccines dampen inflammation and induce tolerogenic regulation. However, achieving the desired potency of tolerogenic vaccines as preventive and therapeutic modalities calls for precise manipulation of the immune microenvironment and control over the tolerogenic responses against the autoantigens, allergens, and/or alloantigens. Engineered nano-/microparticles possess desirable design features that can bolster targeted immune regulation and enhance the induction of antigen-specific tolerance. Thus, particle-based tolerogenic vaccines hold great promise in clinical translation for future treatment of aforementioned immune disorders. In this review, we highlight the main strategies to employ particles as exciting tolerogenic vaccines, with a focus on the particles' role in facilitating the induction of antigen-specific tolerance. We describe the particle design features that facilitate their usage and discuss the challenges and opportunities for designing next-generation particle-based tolerogenic vaccines with robust efficacy to promote antigen-specific tolerance for immunotherapy.

Carbon-Extraction-Induced Biaxial Strain Tuning of Carbon-Intercalated Iridium Metallene for Hydrogen Evolution Catalysis.

Metallene materials with atomic thicknesses are receiving increasing attention in electrocatalysis due to ultrahigh surface areas and distinctive surface strain. However, the continuous strain regulation of metallene remains a grand challenge. Herein, taking advantage of autocatalytic reduction of Cu2+ on biaxially strained, carbon-intercalated Ir metallene, we achieve control over the carbon extraction kinetics, enabling fine regulation of carbon intercalation concentration and continuous tuning of (111) in-plane (-2.0%-2.6%) and interplanar (3.5%-8.8%) strains over unprecedentedly wide ranges. Electrocatalysis measurements reveal the strain-dependent activity toward hydrogen evolution reaction (HER), where weakly strained Ir metallene (w-Ir metallene) with the smallest lattice constant presents the highest mass activity of 2.89 A mg-1Ir at -0.02 V vs reversible hydrogen electrode (RHE). Theoretical calculations validated the pivotal role of lattice compression in optimizing H binding on carbon-intercalated Ir metallene surfaces by downshifting the d-band center, further highlighting the significance of strain engineering for boosted electrocatalysis.

Multi-characteristic tannic acid-reinforced polyacrylamide/sodium carboxymethyl cellulose ionic hydrogel strain sensor for human-machine interaction.

Big data and cloud computing are propelling research in human-computer interface within academia. However, the potential of wearable human-machine interaction (HMI) devices utilizing multiperformance ionic hydrogels remains largely unexplored. Here, we present a motion recognition-based HMI system that enhances movement training. We engineered dual-network PAM/CMC/TA (PCT) hydrogels by reinforcing polyacrylamide (PAM) and sodium carboxymethyl cellulose (CMC) polymers with tannic acid (TA). These hydrogels possess exceptional transparency, adhesion, and remodelling features. By combining an elastic PAM backbone with tunable amounts of CMC and TA, the PCT hydrogels achieve optimal electromechanical performance. As strain sensors, they demonstrate higher sensitivity (GF = 4.03), low detection limit (0.5 %), and good linearity (0.997). Furthermore, we developed a highly accurate (97.85 %) motion recognition system using machine learning and hydrogel-based wearable sensors. This system enables contactless real-time training monitoring and wireless control of trolley operations. Our research underscores the effectiveness of PCT hydrogels for real-time HMI, thus advancing next-generation HMI systems.

Low-Electronegativity Mn-Contraction of PtMn Nanodendrites Boosts Oxygen Reduction Durability.

Platinum metal (PtM, M=Ni, Fe, Co) alloys catalysts show high oxygen reduction reaction (ORR) activity due to their well-known strain and ligand effects. However, these PtM alloys usually suffer from a deficient ORR durability in acidic environment as the alloyed metal is prone to be dissolved due to its high electronegativity. Herein, we report a new class of PtMn alloy nanodendrite catalyst with low-electronegativity Mn-contraction for boosting the oxygen reduction durability of fuel cells. The moderate strain in PtMn, induced by Mn contraction, yields optimal oxygen reduction activity at 0.53 A mg-1 at 0.9 V versus reversible hydrogen electrode (RHE). Most importantly, we show that relative to well-known high-electronegativity Ni-based Pt alloy counterpart, the PtMn nanodendrite catalyst experiences less transition metals' dissolution in acidic solution and achieves an outstanding mass activity retention of 96 % after 10,000 degradation cycles. Density functional theory calculation reveals that PtMn alloys are thermodynamically more stable than PtNi alloys in terms of formation enthalpy and cohesive energy. The PtMn nanodendrite-based membrane electrode assembly delivers an outstanding peak power density of 1.36 W cm-2 at a low Pt loading and high-performance retention over 50 h operations at 0.6 V in H2 -O2 hydrogen fuel cells.

Review of research progress on the role of the effective components of traditional Chinese medicine in sepsis with multiple organ dysfunction.

The concept of sepsis has recently evolved from one of a 'systemic inflammatory response syndrome caused by infection' to a 'severe, potentially fatal organic dysfunction caused by an inadequate or imbalanced host response to infection'. Organ dysfunction is closely related to sepsis. Multiple organ dysfunction syndrome (MODS) is the most serious outcome of sepsis, often leading to a poor prognosis. However, specific drugs for sepsis and MODS caused by sepsis remain undetermined, and the fatality rate is relatively high. Under the guidance of modern medicine, traditional Chinese medicine (TCM) has gained a wealth of experience in the prevention and treatment of sepsis and plays a key role via the effects of its numerous components, pathways and targets. This study used 'Sepsis', 'Organ dysfunction' and 'Traditional Chinese medicine' as strategies for searching the databases of Chinese National Knowledge Infrastructure, Wanfang, PubMed and The Web of Science. This paper presents an overview of the current status of TCM component formulations for preventing and treating sepsis with MODS to provide a theoretical basis for clinical treatment and drug development.

Research Progress and Forensic Application of Human Vascular Finite Element Modeling and Biomechanics.

The finite element method (FEM) is a mathematical method for obtaining approximate solutions to a wide variety of engineering problems. With the development of computer technology, it is gradually applied to the study of biomechanics of human body. The application of the combination of FEM and biomechanics in exploring the relationship between vascular injury and disease, and pathological mechanisms will be a technological innovation for traditional forensic medicine. This paper reviews the construction and development of human vascular FEM modeling, and its research progress on the vascular biomechanics. This paper also looks to the application prospects of FEM modeling in forensic pathology.

Precise synthetic control of exclusive ligand effect boosts oxygen reduction catalysis.

Ligand effect, induced by charge transfer between catalytic surface and substrate in core/shell structure, was widely proved to benefit Pt-catalyzed oxygen reduction reaction by tuning the position of d-band center of Pt theoretically. However, ligand effect is always convoluted by strain effect in real core/shell nanostructure; therefore, it remains experimentally unknown whether and how much the ligand effect solely contributes electrocatalytic activity improvements. Herein, we report precise synthesis of a kind of Pd3Ru1/Pt core/shell nanoplates with exclusive ligand effect for oxygen reduction reaction. Layer-by-layer growth of Pt overlayers onto Pd3Ru1 nanoplates can guarantee no lattice mismatch between core and shell because the well-designed Pd3Ru1 has the same lattice parameters as Pt. Electron transfer, due to the exclusive ligand effect, from Pd3Ru1 to Pt leads to a downshift of d-band center of Pt. The optimal Pd3Ru1/Pt1-2L nanoplates achieve excellent activity and stability for oxygen reduction reaction in alkaline/acid electrolyte.

Gesture Recognition System Using Reduced Graphene Oxide-Enhanced Hydrogel Strain Sensors for Rehabilitation Training.

Gesture recognition systems epitomize a modern and intelligent approach to rehabilitative training, finding utility in assisted driving, sign language comprehension, and machine control. However, wearable devices that can monitor and motivate physically rehabilitated people in real time remain little studied. Here, we present an innovative gesture recognition system that integrates hydrogel strain sensors with machine learning to facilitate finger rehabilitation training. PSTG (PAM/SA/TG) hydrogels are constructed by thermal polymerization of acrylamide (AM), sodium alginate (SA), and tannic acid-reduced graphene oxide (TA-rGO, TG), with AM polymerizing into polyacrylamide (PAM). The surface of TG has abundant functional groups that can establish multiple hydrogen bonds with PAM and SA chains to endow the hydrogel with high stretchability and mechanical stability. Our strain sensor boasts impressive sensitivity (Gauge factor = 6.13), a fast response time (40.5 ms), and high linearity (R2 = 0.999), making it an effective tool for monitoring human joint movements and pronunciation. Leveraging machine learning techniques, our gesture recognition system accurately discerns nine distinct types of gestures with a recognition accuracy of 100%. Our research drives wearable advancements, elevating the landscape of patient rehabilitation and augmenting gesture recognition systems' healthcare applications.

Regorafenib activates oxidative stress by inhibiting SELENOS and potentiates oxaliplatin-induced cell death in colon cancer cells.

Colorectal cancer (CRC) is the third most common cancer, and is one of the leading causes of cancer-related death worldwide. At the time of diagnosis, about 20% of patients with CRC present metastatic disease. Regorafenib, an oral multi-kinase inhibitor, has been demonstrated the efficacy and tolerability in patients with metastatic CRC. Oxaliplatin is a frontline treatment regimen for CRC, and combination treatments with oxaliplatin and other chemotherapeutic agents exert superior therapeutic effects. However, side effects and drug resistance limited their further clinical application. Here, we found that combined treatment with regorafenib and oxaliplatin synergistically enhanced anti-tumor activities in CRC by activating reactive oxygen species (ROS) mediated endoplasmic reticulum (ER) stress, C-Jun-amino-terminal kinase (JNK) and p38 signaling pathways. Regorafenib promoted ROS production by suppressing the expression of selenoprotein S (SELENOS). Knocking down SELENOS sensitized ROS-mediated anti-tumor effects of regorafenib in CRC cells. Furthermore, mouse xenograft models demonstrated that synergistic anti-tumor effects of combined treatment with regorafenib and oxaliplatin. This study provided solid experimental evidences for the combined treatment with regorafenib and oxaliplatin in CRC.

Huntingtin-associated protein 1 ameliorates neurological function rehabilitation by facilitating neurite elongation through TrKA-MAPK pathway in mice spinal cord injury.

Aims: Huntingtin-associated protein 1 (HAP1) is a neuronal protein closely associated with microtubules and might facilitate neurological function rehabilitation. This study aimed to investigate the effects of HAP1 on SCI and the underlying mechanisms. Methods: the spinal cord injury (SCI) mouse model was induced by Allen's method. Then recombinant-HAP1 (r-HAP1) was administrated by intrathecal injection, and the BMS, Thermal nociceptive thresholds, tactile nociceptive thresholds, and neurofibrillary regeneration were identified to inspect the therapy outcome. Then NSCs were isolated from mice on embryonic day 14.5 and induced to differentiate into neurons. The efficiency of axon growth was calculated. Signaling pathway array was conducted to examine the signaling pathways in NSCs treated with r-HAP1. Antagonists and activators of TrkA were used to confirm the role of TrkA of HAP1 intervention both in vitro and in vivo. Results: r-HAP1 ameliorates the neurological function rehabilitation after SCI, and benefits the regain of Tuj in injury spinal cord. Also significantly enhances neurite growth during neuronal differentiation of NSCs; Signaling pathway array and Western blot revealed that r-HAP1 significantly activates the phosphorylation of TrkA-MAPK/ERK in NSCs. TrkA selective inhibitor GW441756 blocks r-HAP1 on TrkA-MAPK/ERK signaling pathway and detracts from axonal growth after neuronal differentiation. TrkA selective activator gambogic amide can mimic the function of r-HAP1 by activating the foregoing pathway. ERK activator U-46619 reverses the blocking effect of GW441756 on r-HAP1. Conclusion: HAP1 activates the TrkA-MAPK signaling pathway and is conducive to neurite elongation during NSC neuronal differentiation; by which to improve the prognosis of spinal cord injury in mice.

Longitudinal relationships between grip strength, subjective memory complaints and cognitive function among middle-aged and older adults in China.

BACKGROUND: Subjective memory complaints are considered an early sign of cognitive decline. Recent evidence shows that grip strength is an important predictor of cognitive function. However, few studies have compared whether one condition is uniquely associated with cognitive function when another condition is controlled for. AIMS: To explore the longitudinal associations of cognitive function with subjective memory complaints and grip strength in middle-aged and older adults, with a particular focus on whether one condition is uniquely associated with cognitive function when another condition is considered. METHODS: A total of 3,877 middle-aged and older adults (aged 45-92 years) from the China Health and Retirement Longitudinal Study reported on their demographic and health status and completed measures of grip strength and subjective memory complaints, as well as a series of cognitive tests, every two years between 2011 and 2015. Generalized estimating equation models were used to assess the relationships between grip strength, subjective memory complaints, and cognitive function. RESULTS: Grip strength was longitudinally associated with cognitive function (ß = 0.021, 95% confidence interval [CI]: 0.011, 0.030, P < 0.001) independent of subjective memory complaints. In contrast, changes in the subjective memory complaints were not related to cognitive function over time (ß = 0.107, 95% CI: - 0.025, 0.238, P = 0.112). Only at baseline subjective memory complaints were associated with poorer cognitive function (ß = - 1.142, 95% CI: - 1.309, - 0.975, P < 0.001). CONCLUSIONS: Grip strength might be a more important clinical correlate of cognitive function decline over time than subjective memory complaints. DISCUSSION: Regular assessment and close monitoring of grip strength might help identify individuals who might be at high risk for cognitive impairment.

Conversion of THz refractive index variation to detectable voltage change realized by a graphene-based Brewster angle device.

The Brewster effect has been previously reported as an essential mechanism for terahertz (THz) wave sensing application. However, generally in a sensing application, a complex rotation apparatus is required for detecting the slight change in Brewster angle. Here, we propose a graphene-based Brewster angle device operating at a specific terahertz frequency capable of sensing the refractive index at a fixed incident angle. In other words, our sensing device could avoid the impact of Brewster angle shift and eliminate the need for high-precision rotating equipment, which is usually required in traditional sensing applications. The conversion from the refractive index to a Volt-level detectable voltage roots from the tunability of graphene's Fermi level in the external electrical field. A linear correlation between the output voltage and the background refractive index is observed and theocratically analyzed. Furthermore, we present the improvement of our device in terms of sensing range and sensitivity by adjusting the permittivity of the dielectric substrate. As a demonstration of our proposed device, a detection range of 1.1-2.4 and a sensitivity of 20.06 V/RIU for refractive index is achieved on a high-resistance silicon substrate operating at 0.3 THz.

Cascaded orbital-oriented hybridization of intermetallic Pd3Pb boosts electrocatalysis of Li-O2 battery.

Catalysts with a refined electronic structure are highly desirable for promoting the oxygen evolution reaction (OER) kinetics and reduce the charge overpotentials for lithium-oxygen (Li-O2) batteries. However, bridging the orbital interactions inside the catalyst with external orbital coupling between catalysts and intermediates for reinforcing OER catalytic activities remains a grand challenge. Herein, we report a cascaded orbital-oriented hybridization, namely alloying hybridization in intermetallic Pd3Pb followed by intermolecular orbital hybridization between low-energy Pd atom and reaction intermediates, for greatly enhancing the OER electrocatalytic activity in Li-O2 battery. The oriented orbital hybridization in two axes between Pb and Pd first lowers the d band energy level of Pd atoms in the intermetallic Pd3Pb; during the charging process, the low-lying 4dxz/yz and 4dz2 orbital of the Pd further hybridizes with 2π* and 5σ orbitals of lithium superoxide (LiO2) (key reaction intermediate), eventually leading to lower energy levels of antibonding and, thus, weakened orbital interaction toward LiO2. As a consequence, the cascaded orbital-oriented hybridization in intermetallic Pd3Pb considerably decreases the activation energy and accelerates the OER kinetics. The Pd3Pb-based Li-O2 batteries exhibit a low OER overpotential of 0.45 V and superior cycle stability of 175 cycles at a fixed capacity of 1,000 mAh g-1, which is among the best in the reported catalysts. The present work opens up a way for designing sophisticated Li-O2 batteries at the orbital level.

Valorisation of food waste for valuable by-products generation with economic assessment.

This study assessed the techno-economic feasibility of a biorefinery for valuable by-products (mainly hydrogen, ethanol and fertilizer) generation from food waste. The plant was designed to be built in Zhejiang province (China) with a processing capacity of 100 t food waste per day. It was found that the total capital investment (TCI) and annual operation cost (AOC) of the plant were US$ 7625549 and US$ 2432290.7 year-1, respectively. After the tax, US$ 3141867.6 year-1 of net profit could be reached. The payback period (PBP) was 3.5 years at a 7% discount rate. The internal rate of return (IRR) and return on investment (ROI) were 45.54% and 43.88%, respectively. Shutdown condition could happen with the feed of food waste less than 7.84 t day-1 (2587.2 t year-1) for the plant. This work was beneficial for attracting interests and even investment for valuable by-products generation from food waste in large scale.

Regorafenib induces NOX5-mediated endoplasmic reticulum stress and potentiates the anti-tumor activity of cisplatin in non-small cell lung cancer cells.

Lung cancer is one of the most commonly diagnosed cancers worldwide. Although cisplatin-based chemotherapy regimens serve a pivotal role in non-small cell lung cancer (NSCLC) treatment, drug resistance and serious side effects limited its further clinical application. Regorafenib, a small-molecule multi-kinase inhibitor, was demonstrated to have promising anti-tumor activity in various solid tumors. In the present study, we found that regorafenib markedly enhanced cisplatin-induced cytotoxicity in lung cancer cells by activating reactive oxygen species (ROS)-mediated endoplasmic reticulum stress (ER Stress), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) signaling pathways. Regorafenib increased ROS generation by promoting NADPH oxidase 5 (NOX5) expression, and knocking down NOX5 attenuated ROS-mediated cytotoxicity of regorafenib in lung cancer cells. Additionally, mice xenograft model validated that synergistic anti-tumor effects of combined treatment with regorafenib and cisplatin. Our results suggested that combination therapy with regorafenib and cisplatin may serve as a potential therapeutic strategy for some NSCLC patients.