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Background Targetable molecular drivers of gastric cancer (GC) metastasis remain largely unidentified, leading to limited targeted therapy options for advanced GC. We aimed to identify molecular drivers for metastasis and devise corresponding therapeutic strategies. Methods We performed an unbiased in vivo genome-wide CRISPR/Cas9 knockout (KO) screening in peritoneal dissemination using genetically engineered GC mouse models. Candidate genes were validated through in vivo transplantation assays using KO cells. We analyzed target expression patterns in GC clinical samples using immunohistochemistry. The functional contributions of target genes were studied through knockdown, KO, and overexpression approaches in tumorsphere and organoid assays. Small chemical inhibitors against Bcl-2 members and YAP were tested in vitro and in vivo . Results We identified Nf2 and Rasa1 as metastasis-suppressing genes through the screening. Clinically, RASA1 mutations along with low NF2 expression define a distinct molecular subtype of metastatic GC exhibiting aggressive traits. NF2 and RASA1 deficiency increased in vivo metastasis and in vitro tumorsphere formation by synergistically amplifying Wnt and YAP signaling in cancer stem cells (CSCs). NF2 deficiency enhanced Bcl-2-mediated Wnt signaling, conferring resistance to YAP inhibition in CSCs. This resistance was counteracted via synthetic lethality achieved by simultaneous inhibition of YAP and Bcl-2. RASA1 deficiency amplified the Wnt pathway via Bcl-xL, contributing to cancer stemness. RASA1 mutation created vulnerability to Bcl-xL inhibition, but the additional NF2 deletion conferred resistance to Bcl-xL inhibition due to YAP activation. The combined inhibition of Bcl-xL and YAP synergistically suppressed cancer stemness and in vivo metastasis in RASA1 and NF2 co-deficiency. Conclusion Our research unveils the intricate interplay between YAP and Bcl-2 family members, which can lead to synthetic lethality, offering a potential strategy to overcome drug resistance. Importantly, our findings support a personalized medicine approach where combined therapy targeting YAP and Bcl-2, tailored to NF2 and RASA1 status, could effectively manage metastatic GC.

Background Skeletal muscle atrophy is a severe condition that involves loss of muscle mass and quality. Drug intake can also cause muscle atrophy. Biguanide metformin is the first‐line and most widely prescribed anti‐diabetic drug for patients with type 2 diabetes. The molecular mechanism of metformin in muscle is unclear. Methods Myostatin expression was investigated at the protein and transcript levels after metformin administration. To investigate the pathways associated with myostatin signalling, we used real‐time polymerase chain reaction, immunoblotting, luciferase assay, chromatin immunoprecipitation assay, co‐immunoprecipitation, immunofluorescence, primary culture, and confocal microscopy. Serum analysis, physical performance, and immunohistochemistry were performed using our in vivo model. Results Metformin induced the expression of myostatin, a key molecule that regulates muscle volume and triggers the phosphorylation of AMPK. AMPK alpha2 knockdown in the background of metformin treatment reduced the myostatin expression of C2C12 myotubes (−49.86 ± 12.03%, P < 0.01) and resulted in increased myotube diameter compared with metformin (+46.62 ± 0.88%, P < 0.001). Metformin induced the interaction between AMPK and FoxO3a, a key transcription factor of myostatin. Metformin also altered the histone deacetylase activity in muscle cells (>3.12‐fold ± 0.13, P < 0.001). The interaction between HDAC6 and FoxO3a induced after metformin treatment. Confocal microscopy revealed that metformin increased the nuclear localization of FoxO3a (>3.3‐fold, P < 0.001). Chromatin immunoprecipitation revealed that metformin induced the binding of FoxO3a to the myostatin promoter. The transcript‐level expression of myostatin was higher in the gastrocnemius (GC) muscles of metformin‐treated wild‐type (WT) (+68.9 ± 10.01%, P < 0.001) and db/db mice (+55.84 ± 6.62%, P < 0.001) than that in the GC of controls (n = 4 per group). Average fibre cross‐sectional area data also showed that the metformin‐treated C57BL/6J (WT) (−31.74 ± 0.75%, P < 0.001) and C57BLKS/J‐db/db (−18.11 ± 0.94%, P < 0.001) mice had decreased fibre size of GC compared to the controls. The serum myoglobin level was significantly decreased in metformin‐treated WT mice (−66.6 ± 9.03%, P < 0.01). Conclusions Our results demonstrate that metformin treatment impairs muscle function through the regulation of myostatin in skeletal muscle cells via AMPK‐FoxO3a‐HDAC6 axis. The muscle‐wasting effect of metformin is more evident in WT than in db/db mice, indicating that more complicated mechanisms may be involved in metformin‐mediated muscular dysfunction.

To investigate the effects of Gastrodia elata Blume (GEB) and 4-hydroxybenzyl alcohol (HBA) on brain damage, GEB or HBA was administered orally for 14 days before middle cerebral artery occlusion (MCAO). After 24 h reperfusion, the proportion of circling was significantly reduced in the GEB (79%) or HBA (69%) group compared to the MCAO group (100%) in the corner test, and the removal time in the adhesive removal test was significantly decreased in the GEB (117 ± 21.0 s) and HBA (101 ± 20.9 s) groups compared to the MCAO group (161 ± 12.6 s). GEB treatment significantly reduced infarct volume compared to the MCAO group. In the GEB and HBA group, necrosis of nerve cells in hippocampus and cortex, expressions of TNF-α and TUNEL positive cells were significantly reduced compared to the MCAO group. These results suggest that GEB and HBA prevents brain damage by anti-inflammatory and anti-apoptotic effects.