Background: Gastric cancer (GC) is one of the most common tumours in East Asia countries and is associated with Helicobacter pylori infection. H. pylori utilizes virulence factors, CagA and VacA, to up‐regulate pro‐inflammatory cytokines and activate NF‐κB signaling. Meanwhile, the PIEZO1 upregulation and cancer‐associated fibroblast (CAF) enrichment were found in GC progression. However, the mechanisms of PIEZO1 upregulation and its involvement in GC progression have not been fully elucidated.Methods: The CAF enrichment and clinical significance were investigated in animal models and primary samples. The expression of NF‐κB and PIEZO1 in GC was confirmed by immunohistochemistry staining, and expression correlation was analysed in multiple GC datasets. GSEA and Western blot analysis revealed the YAP1‐CTGF axis regulation by PIEZO1. The stimulatory effects of CTGF on CAFs were validated by the co‐culture system and animal studies. Patient‐derived organoid and peritoneal dissemination models were employed to confirm the role of the PIEZO1‐YAP1‐CTGF cascade in GC.Results: Both CAF signature and PIEZO1 were positively correlated with H. pylori infection. PIEZO1, a mechanosensor, was confirmed as a direct downstream of NF‐κB to promote the transformation from intestinal metaplasia to GC. Mechanistic studies revealed that PIEZO1 transduced the oncogenic signal from NF‐κB into YAP1 signaling, a well‐documented oncogenic pathway in GC progression. PIEZO1 expression was positively correlated with the YAP1 signature (CTGF, CYR61, and c‐Myc, etc.) in primary samples. The secreted CTGF by cancer cells stimulated the CAF infiltration to form a stiffened collagen‐enrichment microenvironment, thus activating PIEZO1 to form a positive feedback loop. Both PIEZO1 depletion by shRNA and CTGF inhibition by Procyanidin C1 enhanced the efficacy of 5‐FU in suppressing the GC cell peritoneal metastasis.Conclusion: This study elucidates a novel driving PIEZO1‐YAP1‐CTGF force, which opens a novel therapeutic avenue to block the transformation from precancerous lesions to GC. H. pylori‐NF‐κB activates the PIEZO1‐YAP1‐CTGF axis to remodel the GC microenvironment by promoting CAF infiltration. Targeting PIEZO1‐YAP1‐CTGF plus chemotherapy might serve as a potential therapeutic option to block GC progression and peritoneal metastasis.

Background: Cancer‐associated fibroblasts (CAFs), integral to the tumour microenvironment, are pivotal in cancer progression, exhibiting either pro‐tumourigenic or anti‐tumourigenic functions. Their inherent phenotypic and functional diversity allows for the subdivision of CAFs into various subpopulations. While several classification systems have been suggested for different cancer types, a unified molecular classification of CAFs on a single‐cell pan‐cancer scale has yet to be established.Methods: We employed a comprehensive single‐cell transcriptomic atlas encompassing 12 solid tumour types. Our objective was to establish a novel molecular classification and to elucidate the evolutionary trajectories of CAFs. We investigated the functional profiles of each CAF subtype using Single‐Cell Regulatory Network Inference and Clustering and single‐cell gene set enrichment analysis. The clinical relevance of these subtypes was assessed through survival curve analysis. Concurrently, we employed multiplex immunofluorescence staining on tumour tissues to determine the dynamic changes of CAF subtypes across different tumour stages. Additionally, we identified the small molecule procyanidin C1 (PCC1) as a target for matrix‐producing CAF (matCAF) using molecular docking techniques and further validated these findings through in vitro and in vivo experiments.Results: In our investigation of solid tumours, we identified four molecular clusters of CAFs: progenitor CAF (proCAF), inflammatory CAF (iCAF), myofibroblastic CAF (myCAF) and matCAF, each characterised by distinct molecular traits. This classification was consistently applicable across all nine studied solid tumour types. These CAF subtypes displayed unique evolutionary pathways, functional roles and clinical relevance in various solid tumours. Notably, the matCAF subtype was associated with poorer prognoses in several cancer types. The targeting of matCAF using the identified small molecule, PCC1, demonstrated promising antitumour activity.Conclusions: Collectively, the various subtypes of CAFs, particularly matCAF, are crucial in the initiation and progression of cancer. Focusing therapeutic strategies on targeting matCAF in solid tumours holds significant potential for cancer treatment.

Introduction: Prolonged exposure to air polluted with airborne fine particulate matter (PM2.5) can increase respiratory disease risk. Astragaloside IV (AS-IV) is one of the main bioactive substances in the traditional Chinese medicinal herb, Astragalus membranaceus Bunge. AS-IV has numerous pharmacological properties; whereas there are few reports on the prevention of PM2.5-induced lung injury by AS-IV through modulation of the autophagic pathway. This study aimed to investigate the protective effects and the underlying mechanisms of AS-IV in PM2.5-induced lung injury rats and rat alveolar macrophages (NR8383 cells). Methods: The pneumotoxicity model was established by intratracheal injection of PM2.5 in rats, and PM2.5 challenge in NR8383 cells. The severity of lung injury was evaluated by wet weight to dry weight ratio and McGuigan pathology scoring. Inflammatory factors and oxidative stress were detected through ELISA. The expressions of p-PI3K, p-Akt, and p-mTOR proteins were analyzed by immunohistochemistry. Immunofluorescence and transmission electron microscopy were used to detect autophagosomes. The expressions of autophagy marker protein (LC3B and p62), PI3K/Akt/mTOR signaling and NF-κB translocation were detected by Western blot in lung tissue and NR8383 cells. Results: After PM2.5 stimulation, rats showed severe inflammation and oxidative stress, along with inhibition of autophagy in lung tissue. AS-IV not only decreased pulmonary inflammation and oxidative stress by inhibiting nuclear factor kappa B translocation, but also regulated autophagy by inhibiting PI3K/Akt/mTOR signaling. After treatment with 3-methyladenine (a classic PI3K inhibitor, blocking the formation of autophagosomes), the protective effect of AS-IV on PM2.5-induced lung injury was further strengthened. In parallel, using Western blot, immunohistochemistry, and transmission electron microscopy, we demonstrated that AS-IV restore autophagic flux mainly through regulating the degradation of autophagosomes rather than suppressing the formation in vivo and in vitro. Conclusion: Our data indicated that AS-IV protects from PM2.5-induced lung injury in vivo and in vitro by inhibiting the PI3K/Akt/mTOR pathway to regulate autophagy and inflammation.

High altitude pulmonary edema (HAPE) is a potentially fatal condition induced by exposure to high-altitude environment. Eleutheroside B is a naturally active polyphenolic substance that has previously demonstrated anti-inflammatory, antioxidant and antidepressant properties. However, the effects of eleutheroside B on HPAE are unknown. Here, eleutheroside B (50 mg/kg and 100 mg/kg) was applied to HAPE rats. Eleutheroside B alleviated lung edema and decreased levels of tumor necrosis factor-α, interleukin-1β, vascular endothelial growth factor, and total proteins in the bronchoalveolar lavage fluid. Eleutheroside B reversed the acid-base disturbances by HAPE. In addition, eleutheroside B reversed the oxidative stress. Eleutheroside B pretreatment facilitated the translocation of nuclear factor E2-related factor 2 (Nrf2) into the nucleus, contributing to the inhibition of ferroptosis and necroptosis. ML385 confirmed the role of Nrf2 in ferroptosis and necroptosis. Collectively, the beneficial effects of eleutheroside B against HAPE were associated with the inhibition of ferroptosis and necroptosis through Nrf2-antioxidant response signaling.