Non-small cell lung cancer (NSCLC) is the most common form of lung cancer and the leading cause of cancer-related deaths globally. The RNA binding protein Quaking-5 (QKI-5) has been established as a tumor suppressor in NSCLC. Inducing ferroptosis is regarded as an effective therapeutic strategy for cancer treatment, and long non-coding RNA (lncRNA) plays a critical role in the regulation of ferroptosis. However, the relationship between QKI-5-regulated lncRNA and ferroptosis remains uncharacterized in NSCLC. In this study, we discovered that QKI-5 downregulates the oncogenic lncRNA linc01833, which inhibits ferroptosis and promotes NSCLC progression by activating SLC7A11/GPX4 signaling pathway. Mechanistically, QKI-5 negatively regulates the stability of linc01833, leading to increased linc01833 expression in NSCLC. Silencing linc01833 enhanced WW domain-containing E3 ubiquitin protein ligase 1 (WWP1)-mediated ubiquitination of SLC7A11, resulting in decreased SLC7A11 expression, while overexpression of linc01833 produced the opposite effect. Further analyses demonstrated that linc01833 diminished the anti-tumor effect of gemcitabine (GEM) in NSCLC both in vivo and in vitro. Additionally, knocking down linc01833 or SLC7A11 is able to inhibit GEM resistant NSCLC growth. Our findings suggest that targeting linc01833 to induce ferroptosis could enhance the cytotoxic effects of chemotherapeutic agents and may serve as an effective therapeutic strategy for some NSCLC patients.

6-Methoxydihydrosanguinarine is a natural alkaloid derived from medicinal plants that exhibits significant antitumor activity, making it a promising candidate for cancer therapy. However, the exact molecular mechanisms underlying its effects require further investigation. In this study, we investigated the cytotoxicity and underlying mechanisms of 6-Methoxydihydrosanguinarine in human non-small cell lung cancer (NSCLC) cells. Our findings reveal that reactive oxygen species (ROS) accumulation is the key driver of its antitumor activity. Mechanistically, 6-Methoxydihydrosanguinarine activates the JNK signaling pathway and induces endoplasmic reticulum (ER) stress, both of which can be reversed by the ROS scavenger N-acetylcysteine (NAC). Interestingly, 6-Methoxydihydrosanguinarine also activates autophagy, and inhibition of autophagy reverses the JNK and ER stress pathway activation induced by 6-Methoxydihydrosanguinarine. Notably, 6-Methoxydihydrosanguinarine synergistically enhances cisplatin-induced NSCLC cell death, and this synergistic effect is abolished by NAC, highlighting the critical role of ROS accumulation in their combined efficacy. This study systematically elucidates the molecular mechanisms of 6-Methoxydihydrosanguinarine against NSCLC, revealing that, in addition to the JNK and autophagy pathways, ER stress also mediates its antitumor effects. Moreover, our data establish a rationale for exploring 6-Methoxydihydrosanguinarine in NSCLC therapy and highlight its combination with cisplatin as a potentially effective strategy.

KRAS-mutant tumors remain a major challenge in cancer therapy. Although current targeted drugs show initial promise, their efficacy is often limited by the development of resistance. Therefore, identifying effective drug combinations to target KRAS-mutant tumors is of great significance. This study investigates the synergistic potential of romidepsin (RO), a class I HDAC inhibitor, in combination with adagrasib (ADA). In vitro experiments demonstrated that RO exhibits potent antitumor activity, with significant efficacy against KRAS-mutant cells. Mechanistic studies revealed that RO exerts its effect by suppressing NRF2. More importantly, its combination with ADA enhanced cytotoxicity and further suppressed NRF2 expression, resulting in increased ROS levels, induction of cytotoxic autophagy, and inhibition of the downstream AKT pathway. In vivo xenograft models confirmed that the combination of RO and ADA significantly reduced tumor growth. These findings suggest that RO and ADA act synergistically against KRAS-mutant tumors by suppressing NRF2, supporting their potential as a targeted combination strategy for KRAS-driven cancers.

Background Colorectal cancer (CRC) is among the most prevalent malignancies globally, with its incidence continuing to rise in recent years. Sorafenib, a multi-kinase inhibitor, has shown therapeutic effects in advanced CRC. Usenamine A (UD32-3), a natural compound, is isolated from lichens. However, anti-tumor activity of UD32-3 in CRC and its biological functions in anti-CRC activity of sorafenib remain unknown. Purpose This study aims to elucidate the mechanism underlying anti-CRC effects of UD32-3 and its potential to enhance the therapeutic efficacy of sorafenib. Study design and Methods Immunofluorescence assays were employed to investigate reactive oxygen species (ROS) and autophagy levels. Gene knockdown or overexpression was performed using Lipofectamine 3000 reagent, and relative gene and protein expression levels were evaluated by quantitative real-time PCR (qRT-PCR) and Western blot analyses. Molecular docking analysis was performed to investigate the interaction between UD32-3 and superoxide dismutase 2 (SOD2). Mouse xenograft models were employed to evaluate the effects of combination therapy with UD32-3 and sorafenib. Results UD32-3 exerts anti-CRC activity by inducing ROS-mediated autophagy and inhibiting YAP pathway through targeting SOD2. Knocking down SOD2 sufficiently induced ROS generation and autophagy, and inhibited the YAP pathway, thereby enhancing the anti-CRC activity of UD32-3. Conversely, overexpression of SOD2 yielded opposite results, attenuating these effects. Combined treatment with UD32-3 and sorafenib exerted synergistic anti-tumor activities by activating autophagy and inhibiting YAP signaling pathway. Additionally, YAP inhibitor strengthened anti-CRC activity of UD32-3 and sorafenib by inhibiting SOD2 expression, suggesting autophagy-mediated negative feedback loop between SOD2 and YAP. Conclusions UD32-3 has significant druggable potential, and combination treatment of UD32-3 and sorafenib may serve as an effective therapeutic strategy for patients with certain CRC.

Demethoxycurcumin (DMC) has demonstrated remarkable anti-cancer properties across various tumor types. However, its efficacy in hepatocellular carcinoma (HCC) has not yet been established. Interestingly, the type of cell death induced by DMC was distinct from traditional pathways such as apoptosis, ferroptosis, necroptosis, pyroptosis, cuproptosis, and autophagy, indicating a need for further detailed exploration of its mechanisms. Our investigations revealed that DMC treatment led to a marked increase in oxidative stress, as evidenced by the accumulation of reactive oxygen species (ROS). This increase in ROS disrupted the iron-sulfur (Fe-S) cluster, impairing mitochondrial respiration. Additionally, ROS activation markedly reduced the rate of aerobic glycolysis by interfering with key glycolytic enzymes. The resultant inhibition of these bioenergetic pathways led to a significant depletion of ATP. Moreover, DMC activated the ATF4/ATF3/CHOP signaling axis, and the reduction of CHOP levels mitigated the cytotoxic effects of DMC in HCC cells. In conclusion, DMC initiated oxidative stress, which disrupted bioenergetic metabolism and activated the ATF4/ATF3/CHOP signaling pathway, ultimately leading to cell death in HCC cells. These findings suggest that DMC might have a potential role in the treatment of HCC. However, further validation through in vivo models and clinical trials is required to confirm the therapeutic potential of DMC against HCC. Moreover, more work is still needed to further explore the specific form of cell death induced by DMC.

Glutamyl-prolyl-tRNA synthetase 1 (EPRS1) is a key enzyme in protein synthesis and is implicated in various diseases, including inflammation, fibrosis, and cancer. Here, we found that EPRS1 is highly expressed in patients with colon cancer and is positively correlated with poor prognosis. Halofuginone, a derivative of febrifugine extracted from the traditional Chinese herb Dichroa febrifuga, was previously identified as a specific inhibitor of EPRS1. Our research found that halofuginone significantly inhibit the growth of colon cancer cells. Mechanistic investigations demonstrated that halofuginone treatment activates the ATF4-CHOP and JNK signaling pathways in colon cancer cells. Further research revealed that halofuginone inhibits the expression of NRF2, and that high NRF2 expression can reverse halofuginone's anti-colon cancer activity. Importantly, the inhibition of NRF2, along with the activation of the ATF4-CHOP and JNK signaling pathways caused by halofuginone, can be substantially reversed by proline. Additionally, we observed a synergistic antitumor effect when halofuginone was combined with bortezomib, a well-established proteasome inhibitor, in colon cancer cells. These results imply that the halofuginone-bortezomib combination could offer a promising therapeutic option for colon cancer treatment. In summary, our research comprehensively elucidates the molecular mechanisms underlying halofuginone's action against colon cancer and provides new insights into halofuginone-based combination therapies.

Lung cancer represents one of the most lethal malignancies, characterized by the highest incidence and mortality rates globally. Cisplatin-based chemotherapy exerts powerful anti-tumor activities in lung cancer, whereas its clinical application was limited due to the severe side effects. Dihydrotanshinone I (DHTS), a root extract from Salvia miltiorrhiza, exhibits diverse biological functions, encompassing liver protection, anti-inflammatory properties, promotion of osteoclast differentiation, and induction of apoptosis in tumor cells. DHTS exerts anti-tumor effects in various cancers, however, its biological functions in lung cancer are largely unknown. We demonstrated that DHTS synergistically increased the tumor suppressive effects of cisplatin in lung cancer cells by activating reactive oxygen species (ROS)-mediated endoplasmic reticulum stress (ER stress) and c-Jun N-terminal kinase (JNK) signaling pathways, both in vitro and in vivo. Additionally, DHTS induced excessive ROS accumulation by inhibiting the expression of Heat Shock Proteins 60 (HSPD1). Silencing HSPD1 augmented the anti-tumor effects of DHTS in lung cancer cells, primarily through the stimulation of ROS-mediated ER stress and JNK pathways. Our study suggests that DHTS possesses druggable potential, and combined therapy with DHTS and cisplatin may be a promising therapeutic strategy for certain lung cancer patients.

Homeobox B8 (HOXB8) belongs to the HOX family and was essential to the development of colorectal carcinoma. Among the prevalent monoclonal antibodies for treating RAS/BRAF wild-type metastatic colorectal cancer (mCRC) patients, cetuximab stands out, but resistance to cetuximab frequently arises in targeted treatments. Currently, the role of HOXB8 in cetuximab-resistant mCRC remains unclear. By comparing drug-sensitive cell lines (SW48) with drug-resistant cell lines (HCT116, CACO2), we discovered that HOXB8 was substantially expressed in cetuximab-resistant cell lines, and furthermore, in drug-resistant cell lines (HCT116, CACO2), HOXB8 knockdown increased the cytotoxicity of cetuximab via blocking the signal transducer and activator of transcription 3 (STAT3) signaling pathway. Conversely, the excessive expression of HOXB8 reduced the growth suppression in SW48 cells caused by cetuximab by triggering the STAT3 signaling pathway. Conclusively, we conclude that HOXB8 has played an essential role in cetuximab-resistant mCRC and that treating HOXB8 specifically may be a useful treatment approach for certain cetuximab-resistant mCRC patients.

Lung cancer is one of the leading causes of cancer-related deaths worldwide, with non-small cell lung cancer (NSCLC) being the most prevalent subtype. Gemcitabine is a primary clinical option for the treatment of NSCLC. Nevertheless, it encounters challenges including drug resistance and severe adverse effects. High expression of regulator of G protein signaling 2 (RGS2) is associated with poor prognosis in NSCLC. Usenamine A (UD32-3), a natural compound derived from lichen usnea longissimi, exerts anti-tumor activities in certain types of cancer cells, however, its underlying molecular mechanisms in NSCLC are largely unknown. In this study, we demonstrated for the first time that UD32-3 exerts anti-NSCLC activity by targeting RGS2, thereby suppressing Notch1 to induce autophagy and promoting reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress. Suppression of RGS2 inhibited cell growth by inducing ROS-mediated ER stress and Notch1-mediated autophagy in NSCLC, whereas its overexpression had the opposite effects. Additionally, combined therapy with UD32-3 and gemcitabine exerted synergistic anti-NSCLC activity. Our findings suggest that RGS2 is a promising therapeutic target for the treatment of NSCLC, and combined therapy with UD32-3 and gemcitabine might be an alternative therapeutic strategy for certain NSCLC patients.

Adagrasib, a KRASG12C inhibitor, recently received accelerated approval from the US FDA for the treatment of patients diagnosed with KRASG12C-mutated non-small cell lung cancer. Although adagrasib has demonstrated excellent clinical efficacy and good safety, the molecular mechanism underlying the antitumor activity of adagrasib remains elusive. Here, we report that adagrasib treatment markedly inhibited the growth of cells harboring the KRASG12C mutation, whereas the non-KRASG12C cell lines H1299 and PC-9 were also sensitive to adagrasib, indicating that adagrasib exerted off-target effects. Mechanism studies indicated that adagrasib treatment reduced the level of NRF2 via upregulating its ubiquitination, and NRF2 overexpression can reverse the adagrasib-induced cell death in H23 and H1299 cells. Furthermore, adagrasib treatment significantly increased the cellular ROS level and thereby activating autophagy and AKT signaling pathways in H23 and H1299 cells. Importantly, combination of adagrasib with panobinostat demonstrated enhanced antitumor activity in vitro and in vivo. Overall, our data elucidate a novel mechanism of adagrasib, which will be critical for the clinical application of adagrasib.

Ethnopharmacological relevance Tubeimoside-I (TBM) promotes various cancer cell death by increasing the reactive oxygen species (ROS) production. However, the specific molecular mechanisms of TBM and its impact on oxaliplatin-mediated anti-CRC activity are not yet fully understood. Aim of the study To elucidate the therapeutic effect and underlying molecular mechanism of TBM on oxaliplatin-mediated anti-CRC activity. Materials and methods 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation, wound healing assays and flow cytometry were conducted to investigate the changes in cell phenotypes and ROS generation. Real-time quantitative PCR (qRT-PCR) and western blotting were performed to detect the expressions of related mRNA and proteins. Finally, mouse xenograft models demonstrated that synergistic anti-tumor effects of combined treatment with TBM and oxaliplatin. Results The synergistic enhancement of the anti-tumor effects of oxaliplatin in colon cancer cells by TBM involved in the regulation of ROS-mediated endoplasmic reticulum (ER) stress, C-jun-amino-terminal kinase (JNK), and p38 MAPK signaling pathways. Mechanistically, TBM increased ROS generation in colon cancer cells by inhibiting heat shock protein 60 (HSPD1) expression. Knocking down HSPD1 increased TBM-induced antitumor activity and ROS generation in colon cancer cells. The mouse xenograft tumor models further validated that the combination therapy exhibited stronger anti-tumor effects than monotherapy alone. Conclusions Combined therapy with TBM and oxaliplatin might be an effective therapeutic strategy for some CRC patients.

Lung cancer continues to rank as a leading cause of cancer-related mortality worldwide. Despite notable advances in medical research, therapeutic options for advanced-stage lung cancer remain inadequate. Heat shock protein 90 (HSP90) has been identified as a potential therapeutic target in multiple malignancies, such as lung and colon cancers, owing to its pivotal role in stabilizing numerous oncoproteins. Nonetheless, the clinical application of HSP90 inhibitors has faced challenges, including suboptimal efficacy and the development of resistance mechanisms. B-AP15 is a promising small molecule in cancer therapy that functions by inhibiting deubiquitinating enzymes, which regulate protein degradation through the proteasome pathway. In this study, we aim to investigate its combinatorial activity with the HSP90 inhibitor tanespimycin (TAU) in lung cancer cells. The levels of the specified molecules were measured by Western blot analysis. Reactive oxygen species (ROS) levels were determined using the 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA) probe. 53BP1 foci formation and C/EBP homologous protein (CHOP) expression were assessed by immunofluorescence. Autophagic flux was monitored using mRFP-GFP-tagged microtubule-associated protein 1 light chain 3 (LC3) lentivirus. Our findings reveal that the combination of TAU and B-AP15 induces significant synergistic antitumor effects, characterized by substantial accumulation of ROS. This ROS accumulation serves as a crucial mediator of the enhanced therapeutic response elicited by the combination treatment. Mechanistic analyses further demonstrated that the combined treatment induces cell death via activation of endoplasmic reticulum (ER) stress and the c-Jun N-terminal kinase (JNK) pathway. In summary, our study provides robust evidence supporting the potential of combining TAU with B-AP15 as a viable therapeutic option for lung cancer treatment.

BackgroundPolydatin (3,4′,5-trihydroxy-3-β-d-glucopyranoside, PD) is known for its antioxidant and anti-inflammatory properties. Oxaliplatin (OXA)-based chemotherapy is the first-line treatment for metastatic and recurrent colorectal cancer (CRC). However, the lack of selectivity for normal cells often results in side effects. Consequently, the search for anti-cancer components with high efficacy and low cytotoxicity has become a significant focus in recent years.MethodsThe anti-tumor effects of PD, OXA or their combination were assessed by cell viability, colony formation, and wound-healing assays. Reactive oxygen species (ROS) generation was measured by flow cytometry and DNA damage was assessed by immunofluorescence assay. The relative gene and protein expressions were analyzed by quantitative real time-PCR (qRT-PCR) and Western blot assays. Molecular docking analysis predicted the interaction between PD and potential targets.ResultsWe found that PD exerted anti-CRC activity by promoting Nicotinamide Adenine Dinucleotide Phosphate (NADPH) oxidase 5 (NOX5)-mediated ROS production, activating the endoplasmic reticulum (ER) stress, and inducing DNA damage. Knocking down NOX5 attenuated the inhibition of proliferation and colony forming ability induced by PD in colon cancer cells and reversed the expression of C/EBP-homologous protein (CHOP) and activating transcription factor 4 (ATF4) proteins. In addition, combination of PD and OXA synergistically exerted anti-CRC activities by promoting DNA damage and activating ER stress signaling pathway.ConclusionThe combination of PD and OXA could be an effective treatment strategy for certain patients with CRC.

Purpose:Colon cancer, a predominant contributor to global cancer mortality, is characterized by uncontrolled cell growth in the colon or rectum. Therapeutic progress notwithstanding, including targeted therapies and chemotherapy, the survival rate remains unsatisfactory, especially for patients with advanced colon cancer, underscoring the need for novel strategies to enhance treatment efficacy. Materials and Methods:In this study, we employed Western blot analysis to quantify target protein expression levels and immunofluorescence for protein detection and localization. To evaluate drug interactions, we calculated the Combination Index (CI). Intracellular ROS levels were measured using the DCFH-DA probe. Additionally, we generated target gene-knockdown cell lines via recombinant lentivirus transfection. For in vivo validation, we established a xenograft tumor model in nude mice to assess the therapeutic efficacy of the drug combination. Results:In the study, we systematically evaluated the combinatorial potential of clinically approved lenvatinib and bioactive celastrol against colorectal cancer pathogenesis. Our results demonstrated that the combination treatment significantly inhibited cancer cell proliferation by enhancing reactive oxygen species (ROS) generation. This oxidative stress activated the ATF4-CHOP and JNK signaling pathways, ultimately inducing cell apoptosis as the main cause of death phenomenon. Conclusion:Our research demonstrates that celastrol potentiates lenvatinib's anti-tumor effects in colon cancer by inducing ROS-dependent ER stress and triggering phosphorylation-dependent JNK pathway activation. These findings revealing a promising combinatorial strategy to enhance therapeutic efficacy in colorectal carcinoma.

Non‑small cell lung cancer (NSCLC) is one of the major causes of cancer‑related death worldwide. Cisplatin is a front‑line chemotherapeutic agent in NSCLC. Nevertheless, subsequent harsh side effects and drug resistance limit its further clinical application. Polydatin (PD) induces apoptosis in various cancer cells by generating reactive oxygen species (ROS). However, underlying molecular mechanisms of PD and its effects on cisplatin‑mediated antitumor activity in NSCLC remains unknown. MTT, colony formation, wound healing analyses and flow cytometry was employed to investigate the cell phenotypic changes and ROS generation. Relative gene and protein expressions were evaluated by reverse transcription‑quantitative PCR and western blot analyses. The antitumor effects of PD, cisplatin and their combination were evaluated by mouse xenograft model. In the present study, it was found that PD in combination with cisplatin synergistically enhances the antitumor activity in NSCLC by stimulating ROS‑mediated endoplasmic reticulum stress, and the C‑Jun‑amino‑terminal kinase and p38 mitogen‑activated protein kinase signaling pathways. PD treatment elevated ROS generation by promoting expression of NADPH oxidase 5 (NOX5), and NOX5 knockdown attenuated ROS‑mediated cytotoxicity of PD in NSCLC cells. Mice xenograft model further confirmed the synergistic antitumor efficacy of combined therapy with PD and cisplatin. The present study exhibited a superior therapeutic strategy for some patients with NSCLC by combining PD and cisplatin.

Thioredoxin reductase 1 (TrxR1) has emerged as a promising target for cancer therapy. In our previous research, we discovered several new TrxR1 inhibitors and found that they all have excellent anti-tumor activity. At the same time, we found these TrxR1 inhibitors all lead to an increase in AKT phosphorylation in cancer cells, but the detailed role of AKT phosphorylation in TrxR1 inhibitor-mediated cell death remains unclear. In this study, we identified the combination of AKT and TrxR1 inhibitor displayed a strong synergistic effect in colon cancer cells. Furthermore, we demonstrated that the synergistic effect of auranofin (TrxR1 inhibitor) and MK-2206 (AKT inhibitor) was caused by ROS accumulation. Importantly, we found that ATM inhibitor KU-55933 can block the increase of AKT phosphorylation caused by auranofin, and exhibited a synergistic effect with auranofin. Taken together, our study demonstrated that the activation of ATM/AKT pathway is a compensatory mechanism to cope with ROS accumulation induced by TrxR1 inhibitor, and synergistic targeting of TrxR1 and ATM/AKT pathway is a promising strategy for treating colon cancer.

Background Previous research has suggested potential links between amino acids and metabolic dysfunction-associated steatotic liver disease (MASLD), but the precise roles of amino acids in MASLD development are not well understood. This study aimed to obtain insights into the relationships between circulating amino acids and MASLD.Methods Utilizing data from the UK Biobank, we examined the observational associations of ten amino acids with MASLD in a cohort of 72,626 MASLD cases and 128,102 controls. Bi-directional two-sample Mendelian randomization (MR) was conducted using genome-wide association study data to investigate the causal relationships between amino acids and MASLD. Multiple MR methods comprising MR-Egger and MR-PRESSO were applied to assess pleiotropy and heterogeneity, and multivariable MR was conducted to evaluate the impacts of body mass index (BMI) on these associations. Survival analysis assessed the link between baseline amino acid levels and the risk of major outcomes.Results We identified nine amino acids significantly associated with MASLD in the observational study. The genetic predisposition towards higher leucine (odds ratio (OR) [95% confidence interval (CI)]: 2.1 [1.4, 3.2]), valine (OR [95% CI]: 1.8 [1.3, 2.7]), and alanine (OR [95% CI]: 1.4 [1.1, 1.8]) levels were significantly associated with MASLD. By contrast, the genetic predisposition for increased MASLD risk was significantly associated with phenylalanine (beta = 0.05, p = 4.0×10-4). Further analysis showed that valine may mediate the association between BMI and MASLD, and may also have an exclusive effect on MASLD in addition to the effect of obesity (beta = 1.3, p = 1.9×10-4). Elevated phenylalanine levels in MASLD patients were linked with an increased risk of metabolic dysfunction-associated steatohepatitis (MASH), hepatocellular carcinoma, cirrhosis, heart failure, stroke, and mortality.Conclusion We found genetic associations between circulating branched-chain amino acids, particularly leucine and valine, and MASLD, independent of obesity. Phenylalanine was identified as a potential biomarker for MASLD prognostic complications. These results highlight the importance of amino acid metabolism in MASLD as well as suggest new possibilities for research and therapeutic intervention.### Competing Interest StatementThe authors have declared no competing interest.### Funding StatementJ.L. is supported by a Novo Nordisk Postdoctoral Fellowship Programme run in partnership with the University of Oxford. Y. Z is supported by Discipline Cluster of Oncology, Wenzhou Medical University, China (No.z2-2023024).### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:All participants provided electronically signed informed consent, and the study was approved by the North West Multi-centre Research Ethics Committee, Patient Information Advisory Group, and Community Health Index Advisory Group. The current study is part of UK Biobank project 61054.I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.Yes

Lung cancer is one of the most lethal diseases in the world.Although there has been significant progress in the treatment of lung cancer, there is still a lack of effective strategies for advanced cases.Lenvatinib, a multi-targeted tyrosine kinase inhibitor, has achieved much attention due to its antitumor properties.Nevertheless, the use of lenvatinib is restricted by the characteristics of poor efficacy and drug resistance.In this study, we assessed the effectiveness of lenvatinib combined with thioredoxin reductase 1 (TrxR1) inhibitors in human lung cancer cells.Our results indicate that the combination therapy involving TrxR1 inhibitors and lenvatinib exhibited significant synergistic antitumor effects in human lung cancer cells.Moreover, siTrxR1 also showed significant synergy with lenvatinib in lung cancer cells.Mechanically, we demonstrated that ROS accumulation significantly contributes to the synergism between lenvatinib and TrxR1 inhibitor auranofin.Furthermore, the combination of lenvatinib and auranofin can activate endoplasmic reticulum stress and JNK signaling pathways to achieve the goal of killing lung cancer cells.Importantly, combination therapy with lenvatinib and auranofin exerted a synergistic antitumor effect in vivo.To sum up, the combination therapy involving lenvatinib and auranofin may be a potential strategy for treating lung cancer.

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.