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Schisantherin A (Sch A), a compound derived from Schisandra chinensis, has anti-inflammatory, antitumor, neuroprotective and antifibrotic properties. However, to the best of our knowledge, the role of Sch A in non-small cell lung cancer (NSCLC) has not yet been reported. The purpose of the present study was to determine whether Sch A can prevent the development of NSCLC and to elucidate the underlying mechanisms involved. The results of the present study demonstrated that Sch A inhibited the viability of A549 and HCC827 cells. Furthermore, Sch A increased the intracellular Fe2+ level, reduced the mitochondrial membrane potential and depleted the glutathione content in lung cancer cells. These effects were reversed by the ferroptosis inhibitors ferrostatin-1 and deferoxamine. Bioinformatics analysis and reverse transcription-quantitative PCR results suggested that Sch A increased the mRNA levels of the transcription factor yes-associated protein (YAP). Additionally, Sch A upregulated the expression of YAP and ferroptosis-related proteins, including acyl-CoA synthase long-chain family member 4 (ACSL4) and transferrin receptor (TfR), in lung cancer cells. Silencing of YAP led to the downregulation of its downstream targets, ACSL4 and TfR, even in the presence of Sch A. In vivo, Sch A significantly inhibited subcutaneous tumor growth in nude mice. In conclusion, Sch A may activate the YAP/ACSL4/TfR signaling axis to induce ferroptosis in NSCLC cells, positioning it as a potential small-molecule therapeutic agent for NSCLC.

Recent evidence from cancer research indicates that lactate exerts a suppressive effect on innate immune responses in cancer. This study investigated the mechanisms by which lactate suppresses macrophage pro-inflammatory responses. Macrophages [Raw 264.7 and bone marrow derived macrophages (BMDMs)] were treated with LPS in the presence or absence of lactate. Pro-inflammatory cytokines, NF-κB and YAP activation and nuclear translocation were examined. Our results show that lactate significantly attenuates LPS stimulated macrophage TNF-α and IL-6 production. Lactate also suppresses LPS stimulated macrophage NF-κB and YAP activation and nuclear translocation in macrophages. Interestingly, YAP activation and nuclear translocation are required for LPS stimulated macrophage NF-κB activation and TNFα production. Importantly, lactate suppressed YAP activation and nuclear translocation is mediated by GPR81 dependent AMKP and LATS activation which phosphorylates YAP, resulting in YAP inactivation. Finally, we demonstrated that LPS stimulation induces an interaction between YAP and NF-κB subunit p65, while lactate decreases the interaction of YAP and NF-κB, thus suppressing LPS induced pro-inflammatory cytokine production. Our study demonstrates that lactate exerts a previously unknown role in the suppression of macrophage pro-inflammatory cytokine production GPR81 mediated YAP inactivation, resulting in disruption of YAP and NF-κB interaction and nuclear translocation in macrophages.

Objectives In recent years, cellular senescence has attracted a lot of interest in researchers due to its involvement in non‐alcoholic fatty liver disease (NAFLD). However, the mechanism of cellular senescence is not clear. The purpose of this study was to investigate the effect of curcumol on hepatocyte senescence in NAFLD and the molecular mechanisms implicated. Materials and methods LVG Golden Syrian hamsters, C57BL/6J mice and human hepatocyte cell line LO2 were used. Cellular senescence was assessed by analyses of senescence marker SA‐β‐gal, p16 and p21, H3K9me3, γ‐H2AX and telomerase activity. Results The results showed that curcumol could inhibit hepatocyte senescence in both in vivo and in vitro NAFLD models, and the mechanism might be related to its regulation of ferritinophagy and subsequent alleviation of iron overload. Moreover, overexpression of nuclear receptor coactivator 4 (NCOA4) weakened the effect of curcumol on ferritinophagy‐mediated iron overload and cellular senescence. Furthermore, we demonstrated that curcumol reduced the expression of NCOA4 by Yes‐associated protein (YAP). In addition, depression of YAP could impair the effect of curcumol on iron overload and cellular senescence. Conclusion Our results clarified the mechanism of curcumol inhibition of hepatocyte senescence through YAP/NCOA4 regulation of ferritinophagy in NAFLD. These findings provided a promising option of curcumol to regulate cellular senescence by target YAP/NCOA4 for the treatment of NAFLD. Curcumol inhibited hepatocyte senescence by suppressing ferritinophagy‐mediated iron overload. Furthermore, this effect of curcumol is related to the regulation of YAP/NCOA4 in NAFLD models.

CHO cells are extensively employed in biological drug industry to manufacture therapeutic proteins. Nevertheless, production of biopharmaceuticals faces obstacles such as limited growth and inadequate productivity. Employing host cell engineering techniques for CHO cells serves as a valuable approach to address the constraints encountered in biologics manufacturing. Despite advancements, most techniques focus on specific genes to address individual cellular challenges. The significance of YAP, transcriptional co-activator, cannot be overstated due to its involvement in regulating organ size and tumor formation. YAP’s influence extends to various cellular processes and is regulated by kinase cascade in the Hippo pathway, which phosphorylates serine residues in specific LATS recognition motifs. Activation of YAP has been observed to impact both the size and quantity of cells. This research investigates the effects of YAP5SA on proliferation, apoptosis, and productivity in CHO-K1 cells. YAP5SA, with mutations in all five LATS-target sites, is selected for its heightened activity and resistance to repression through the Hippo-LATS1/2 kinase signaling pathway. Plasmid harboring YAP5SA was transfected into EPO-CHO and the influence of YAP5SA overexpression was investigated. According to our findings, transfection of EPO-CHO cells with YAP5SA exhibited a substantial enhancement in CHO cell productivity, resulting in a 3-fold increase in total protein and EPO, as well as a 1.5-fold increase in specific productivity. Additionally, it significantly contributes in augmenting viability, size, and proliferation. Overall, the findings of this study exemplify the potential of utilizing YAP5SA to impact particular cellular mechanisms, thereby presenting an avenue for customizing cells to fulfill production demands. Key points • YAP5SA in CHO cells boosts growth, reduces apoptosis, and significantly improves productivity. • YAP5SA regulates genes involved in proliferation, survival, and mTOR activation. • YAP5SA increases productivity by improving cell cycle, c-MYC expression, and mTOR pathway.

The mechanical signals within the extracellular matrix (ECM) regulate cell growth, proliferation and differentiation, and integrins function as the hub between the ECM and cellular actin. Focal adhesions (FAs) are multi-protein, integrin-containing complexes, acting as tension-sensing anchoring points that bond cells to the extracellular microenvironment. Talin-1 serves as the central protein of FAs that participates in the activation of integrins and connects them with the actin cytoskeleton. As a cytoplasmic protein, Talin-1 consists of a globular head domain and a long rod comprised of a series of α-helical bundles. The unique structure of the Talin-1 rod domain permits folding and unfolding in response to the mechanical stress, revealing various binding sites. Thus, conformation changes of the Talin-1 rod domain enable the cell to convert mechanical signals into chemical through multiple signaling pathways. The present review discusses the binding partners of Talin-1, their interactions, effects on the cellular processes, and their possible roles in diseases.

Verteporfin (VP) has long been clinically used to treat age-related macular degeneration (AMD) through photodynamic therapy (PDT). Recent studies have reported a significant anti-tumor effect of VP as well. Yes-associated protein (YAP) is a pro-tumorigenic factor that is aberrantly expressed in various cancers and is a central effector of the Hippo signaling pathway that regulates organ size and tumorigenesis. VP can inhibit YAP without photoactivation, along with suppressing autophagy, and downregulating germinal center kinase-like kinase (GLK) and STE20/SPS1-related proline/alanine-rich kinase (SPAK). In addition, VP can induce mitochondrial damage and increase the production of reactive oxygen species (ROS) upon photoactivation, and is an effective photosensitizer (PS) in anti-tumor PDT. We have reviewed the direct and adjuvant therapeutic action of VP as a PS, and its YAP/TEA domain (TEAD)-dependent and independent pharmacological effects in the absence of light activation against cancer cells and solid tumors. Based on the present evidence, VP may be repositioned as a promising anti-cancer chemotherapeutic and adjuvant drug.

The progression and malignancy of many tumors are associated with increased tissue stiffness. Conversely, the oncogenically transformed cells can be confined in soft stroma. Yet, the underlying mechanisms by which soft matrix confines tumorigenesis and metastasis remain elusive. Here, we show that pancreatic cancer cells are suppressed in the soft extracellular matrix, which is associated with YAP1 degradation through autophagic-lysosomal pathway rather than Hippo signal mediated proteasome pathway. In the soft stroma, PTEN is upregulated and activated, which consequently promotes lysosomal biogenesis, leading to the activation of cysteine-cathepsins for YAP1 degradation. In vitro, purified cathepsin L can directly digest YAP1 under acidic conditions. Lysosomal stress, either caused by chloroquine or overexpression of cystatin A/B, results in YAP1 accumulation and malignant transformation. Likewise, liver fibrosis induced stiffness can promote malignant potential in mice. Clinical data show that down-regulation of lysosomal biogenesis is associated with pancreatic fibrosis and stiffness, YAP1 accumulation, and poor prognosis in PDAC patients. Together, our findings suggest that soft stroma triggers lysosomal flux-mediated YAP1 degradation and induces cancer cell dormancy. Graphical Abstract

The purpose of this study was to investigate whether Yes‐associated protein (YAP) activation and proliferation of retinal Müller cells play a role in the development of TGF‐β‐induced retinal fibrosis. We studied the effects of YAP activation on retinal fibrosis in diabetic rats and human retinal Müller cells (hMCs) in vitro. The retinal expression of YAP and fibrogenic molecules in rats was detected using Western blotting and immunohistochemistry. After treatment with transforming growth factor‐β1 (TGF‐β1), the levels of fibrogenic molecules, and the activation of YAP and PI3K/Akt signalling pathway in hMCs were detected with Western blotting. The effect of YAP on retinal fibrotic changes was evaluated using YAP knockdown experiments and YAP inhibitors. Results showed that YAP expression was increased in the retina of diabetic rats along with increased retinal fibrosis. In cultured hMCs, YAP inhibition suppressed TGF‐β1‐stimulated hMC differentiation to myofibroblasts and extracellular matrix (ECM) production, while YAP activation promoted hMC differentiation and ECM production independent of TGF‐β1. Furthermore, hMCs cultured on a gel with greater stiffness differentiated into myofibroblasts in a YAP‐dependent manner. In diabetic rats, treatment with the YAP inhibitor verteporfin suppressed retinal fibrogenesis. In addition, the TGF‐β1‐induced PI3K/Akt signalling pathway mediated YAP activation as well as expression of fibrogenic molecules. The interaction between ECM stiffness and YAP forms a feed‐forward process leading to retinal fibrosis. Our work highlights YAP as an essential regulator of pro‐fibrotic responses in TGF‐β‐induced retinal fibrosis.

Radiotherapy has played a limited role in the treatment of non-small cell lung cancer (NSCLC) due to the risk of tumour radioresistance. We previously established the radioresistant non-small cell lung cancer (NSCLC) cell line H460R. In this study, we identified differentially expressed genes between these radioresistant H460R cells and their radiosensitive parent line. We further evaluated the role of a differentially expressed gene, ITGB1, in NSCLC cell radioresistance and as a potential target for improving radiosensitivity. The radiosensitivity of NSCLC cells was evaluated by flow cytometry, colony formation assays, immunofluorescence, and Western blotting. Bioinformatics assay was used to identify the effect of ITGB1 and YAP1 expression in NSCLC tissues. ITGB1 mRNA and protein expression levels were higher in H460R than in the parental H460 cells. We observed lower clonogenic survival and cell viability and a higher rate of apoptosis of ITGB1-knockdown A549 and H460R cells than of wild type cells post-irradiation. Transfection with an ITGB1 short hairpin (sh) RNA enhanced radiation-induced DNA damage and G2/M phase arrest. Moreover, ITGB1 induced epithelial-mesenchymal transition (EMT) of NSCLC cells. Silencing ITGB1 suppressed the expression and intracellular translocation of Yes-associated protein 1 (YAP1), a downstream effector of ITGB1. ITGB1 may induce radioresistance via affecting DNA repair and YAP1-induced EMT. Taken together, our data suggest that ITGB1 is an attractive therapeutic target to overcome NSCLC cell radioresistance.

The Yes-associated protein (YAP) oncoprotein has been linked to both metastases and resistance to targeted therapy of lung cancer cells. We aimed to investigate the effect of YAP pharmacological inhibition, using YAP/TEA domain (TEAD) transcription factor interaction inhibitors in chemo-resistant lung cancer cells. YAP subcellular localization, as a readout for YAP activation, cell migration, and TEAD transcription factor functional transcriptional activity were investigated in cancer cell lines with up-regulated YAP, with and without YAP/TEAD interaction inhibitors. Parental (A549) and paclitaxel-resistant (A549R) cell transcriptomes were analyzed. The half-maximal inhibitory concentration (IC 50 ) of paclitaxel or trametinib, which are Mitogen-Activated protein kinase and Erk Kinase (MEK) inhibitors, combined with a YAP/TEAD inhibitor (IV#6), was determined. A three-dimensional (3D) microfluidic culture device enabled us to study the effect of IV#6/paclitaxel combination on cancer cells isolated from fresh resected lung cancer samples. YAP activity was significantly higher in paclitaxel-resistant cell lines. The YAP/TEAD inhibitor induced a decreased YAP activity in A549, PC9, and H2052 cells, with reduced YAP nuclear staining. Wound healing assays upon YAP inhibition revealed impaired cell motility of lung cancer A549 and mesothelioma H2052 cells. Combining YAP pharmacological inhibition with trametinib in K-Ras mutated A549 cells recapitulated synthetic lethality, thereby sensitizing these cells to MEK inhibition. The YAP/TEAD inhibitor lowered the IC 50 of paclitaxel in A549R cells. Differential transcriptomic analysis of parental and A549R cells revealed an increased YAP/TEAD transcriptomic signature in resistant cells, downregulated upon YAP inhibition. The YAP/TEAD inhibitor restored paclitaxel sensitivity of A549R cells cultured in a 3D microfluidic system, with lung cancer cells from a fresh tumor efficiently killed by YAP/TEAD inhibitor/paclitaxel doublet. Evidence of the YAP/TEAD transcriptional program’s role in chemotherapy resistance paves the way for YAP therapeutic targeting.