Tumor chemoresistance is often a major cause for the failure of chemotherapy. The resistance of hepatocellular carcinoma (HCC) cells to sorafenib significantly limits its therapeutic effect in HCC patients. For the first time, we found that FXYD domain-containing ion transport regulator 5 (FXYD5) is highly expressed in sorafenib-resistant HCC cells. In addition, the protein expression level of FXYD5 was markedly higher in HCC tissues than in paracancerous tissues. Remarkably, downregulation of FXYD5 expression in Huh7/sora cells reversed their resistance to sorafenib. Moreover, overexpression of FXYD5 reduced the sensitivity of HCC cells to sorafenib, while the downregulation of its expression in HCC cells had the opposite effect. We also found abnormal activation of the Akt/mTOR signaling pathway in Huh7/sora cells. Furthermore, MK2206, an Akt inhibitor, was found to significantly increase the sensitivity of HCC cells to sorafenib. More importantly, the expression level of p-Akt was positively correlated with the expression of FXYD5 in HCC tissues. Therefore, mechanistically, FXYD5 enhances the resistance of HCC cells to sorafenib by activating the Akt/mTOR signaling pathway. In conclusion, this study showed that the activation of the FXYD5/Akt/mTOR signaling axis plays key role in the resistance of HCC cells to sorafenib, and FXYD5 may represent a new potential target for HCC therapy.

Background: Breast cancer has now become the most prevalent cancer worldwide. Existing therapeutic agents are generally accompanied by significant side effects. Here, we highlight Saikosaponin A (SSA), a promising natural metabolite characterized by low toxicity, demonstrating significant efficacy against breast cancer through the induction of cellular senescence.Methods: The antitumor property of SSA was determined via MTT colorimetric assay, 5-ethynyl-2′-deoxyuridine (EdU) incorporation assay, colony formation, and propidium iodide (PI) staining in vitro, as well as xenograft in vivo model. A network approach was used to predict potential targets of SSA reevant for a potential anti-tumor effect and verified through senescence-associated β-galactosidase (SA-β-gal), flow-cytometry analysis, RT-PCR, Western blotting, and immuno-histochemistry assay.Results: SSA significantly suppressed proliferation and triggered cell cycle arrest of SUM159PT and MDA-MB-231 cells. Revealed by network analysis, cellular senescence, and phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway were implemented in the anti-tumor effects of SSA. SSA-stimulated senescence was associated with increased ROS production, distinct senescence-associated secretory phenotype (SASP), and restricted PI3K/Akt signaling, as well as p21 and p53 accumulation. Furthermore, SSA displayed inhibitory effects on tumor growth with minimal toxicity in animal studies, accompanied by activated biomarkers of cellular senescence and decreased expression of p-Akt and p-PI3K.Conclusion: Taken together, based on the preliminary results of network analysis and further experimental validation, this study revealed that SSA significantly induced cell cycle arrest and senescence, and the inhibition of ROS-mediated PI3K/Akt pathway may be the potential mechanism in this process.

Background: Chemotherapy is one of the common treatments for breast cancer. The induction of cancer stem cells (CSCs) is an important reason for chemotherapy failure and breast cancer recurrence. Astragaloside IV (ASIV) is one of the effective components of the traditional Chinese medicine (TCM) Astragalus membranaceus, which can improve the sensitivity of various tumors to chemotherapy drugs. Here, we explored the sensitization effect of ASIV to chemotherapy drug paclitaxel (PTX) in breast cancer from the perspective of CSCs. Methods: The study included both in vitro and in vivo experiments. CSCs from the breast cancer cell line MCF7 with stem cell characteristics were successfully induced in vitro. Cell viability and proliferation were detected using the Cell Counting Kit-8 (CCK-8) and colony formation assays, and flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) methods were performed to detect cell apoptosis. Stemness-related protein expression was determined by western blotting (WB) and immunohistochemistry (IHC). Body weight, histopathology, and visceral organ damage of mice were used to monitor drug toxicity. Results: The expression of stemness markers including Sox2, Nanog, and ALDHA1 was stronger in MCF7-CSCs than in MCF7. PTX treatment inhibited the proliferation of tumor cells by promoting cell apoptosis, whereas the stemness of breast cancer stem cells (BCSCs) resisted the effects of PTX. ASIV decreased the stemness of BCSCs, increased the sensitivity of BCSCs to PTX, and synergistically promoted PTX-induced apoptosis of breast cancer cells. Our results showed that the total cell apoptosis rate increased by about 25% after adding ASIV compared with BCSCs treated with PTX alone. The in vivo experiments demonstrated that ASIV enhanced the ability of PTX to inhibit the growth of breast cancer. WB and IHC showed that ASIV reduced the stemness of CSCs. Conclusions: In this study, the resistance of breast cancer to PTX was attributed to the existence of CSCs; ASIV weakened the resistance of MCF7-CSCs to PTX by significantly attenuating the hallmarks of breast cancer stemness and improved the efficacy of PTX.

Background: Depression promotes breast cancer progression. Given the lack of specific targets for depression-associated breast cancer, there are currently no therapeutic drugs for this type of breast cancer. Methods: Transcriptomic analysis was conducted to identify and functionally annotate genes with differential expression in breast cancer patients exhibiting depressive symptoms. Subsequently, Mendelian randomization was employed to investigate the causal associations between these pivotal genes and breast cancer, thereby validating their potential roles as therapeutic targets. Furthermore, molecular docking techniques were utilized to screen for candidate compounds that may exert therapeutic effects on depression-associated breast cancer. The efficacy of the selected compounds was further assessed using both in vitro cellular experiments and in vivo animal models. Results: We identified IL-8 as a key gene involved in depression-mediated breast cancer progression using transcriptomics. Mendelian randomized analysis suggested that high IL-8 expression promoted breast cancer progression. Further studies demonstrated that IL-8 mediated the breast cancer-promoting effect of depression through the receptor CXCR2. Evidence from both in vitro and in vivo experiments indicates that senkyunolide H may exert its therapeutic effect by regulating CXCR2, thereby counteracting the protumor effects associated with depression in breast cancer. Conclusion: Depression activates CXCR2-mediated breast cancer cell proliferation through IL-8, and senkyunolide H regulates CXCR2 and inhibits its ability to block the cancer-promoting effects of depression, ultimately inhibiting the growth of breast cancer in the context of depression. Graphical

Background: Gut microbiota, bile acid metabolism, and their derived metabolites are critical regulators of intestinal inflammation in inflammatory bowel disease (IBD). While microRNA-29a (miR-29a) is a recognized epigenetic regulator of intestinal inflammation, its role in shaping microbiota-driven bile acid metabolism, particularly secondary bile acid production, remains unclear. This study aimed to investigate how miR-29a regulates microbiota-bile acid axis, with an emphasis on lithocholic acid (LCA) and its anti-inflammatory effects in colitis. Methods: Colitis was induced in wild-type and Mir29a/Mir29b-1 locus-deficient mice using dextran sulfate sodium (DSS), and disease severity, colonic injury, and inflammatory responses were assessed. Fecal microbiota composition and bile acid profiles were characterized using 16S rRNA gene sequencing and targeted metabolomics. Alterations in bile acids were further examined in relation to disease severity. In vitro , Caco-2 cells were used to evaluate the anti-inflammatory effects of LCA under modulation of miR-29a expression. Results: MiR-29a/b1 deficiency significantly exacerbated DSS-induced disease severity, colonic injury, inflammatory responses, and epithelial ultrastructural damage. KO-DSS mice exhibited gut microbiota dysbiosis, with reduced microbial diversity and altered community structure. Targeted metabolomics revealed impaired primary-to-secondary BA biotransformation, characterized by chenodeoxycholic acid (CDCA) accumulation and a reduced LCA/CDCA ratio. In vitro , LCA supplementation attenuated DSS-induced pro-inflammatory gene expression, whereas this protective effect was partially diminished by miR-29a inhibition. Conclusions: These results support a role for miR-29a in maintaining gut microbial bile acid homeostasis during colitis and contributing to the epithelial anti-inflammatory response to LCA. Together, these findings link host microRNA regulation to microbiota-derived BA function and may inform future precision strategies for IBD.