Hepatocellular carcinoma is a highly fatal disease and threatens human health seriously. Fluid shear stress (FSS), which is caused by the leakage of plasma from abnormally permeable tumor blood vessels and insufficient lymphatic drainage, has been identified as contributing pathologically to cancer metastasis. Autophagy and epithelial–mesenchymal transition (EMT) are both reported to be involved in cancer cell migration and invasion, but little has been revealed about the interaction between autophagy and EMT under a tumor mechanical microenvironment. Here, we identified that exposure to 1.4 dyne/cm2 FSS could promote the formation of autophagosomes and significantly increase the expressions of autophagy‐related markers of beclin1 and ATG7, and the ratio of LC3Ⅱ/Ⅰ in both of HepG2 and QGY‐7703 cells. The FSS loading also elevated the levels of mesenchymal markers N‐cadherin, Vimentin, Twist, Snail, and β‐catenin, while the epithelial markers E‐cadherin showed a decrease. Once the autophagy was blocked by 3‐methyladenine (3‐MA) or knocking ATG5 down, the occurrence of FSS‐induced EMT was inhibited dramatically according to the expression and translocation of E‐cadherin, N‐cadherin, and β‐catenin. Given the effect of EMT on cell migration, we observed that inhibition of autophagy could impede FSS‐induced cell migration. Collectively, this study demonstrated that autophagy played a crucial role in FSS‐induced EMT and cell migration in hepatocellular carcinoma.

Rationale: Atherosclerosis is characterized by lipid accumulation, plaque formation, and artery stenosis. The pharmacological treatment is a promising therapy for atherosclerosis, but this approach faces major challenges such as targeted drug delivery, controlled release, and non-specific clearance. Methods: Based on the finding that the cathepsin k (CTSK) enzyme is enriched in atherosclerotic lesions, we constructed an integrin α v β 3 targeted and CTSK-responsive nanoparticle to control the release of rapamycin (RAP) locally. The targeted and responsive nanoparticles (T/R NPs) were engineered by the self-assembly of a targeting polymer PLGA-PEG-c(RGDfC) and a CTSK-sensitive polymer PLGA-Pep-PEG. PLGA-Pep-PEG was also modified with a pair of FRET probe to monitor the hydrolysis events. Results: Our results indicated that RAP@T/R NPs accelerated the release of RAP in response to CTSK stimulation in vitro , which significantly inhibited the phagocytosis of OxLDL and the release of cytokines by inflammatory macrophages. Additionally, T/R NPs had prolonged blood retention time and increased accumulation in the early and late stage of atherosclerosis lesions. RAP@T/R NPs significantly blocked the development of atherosclerosis and suppressed the systemic and local inflammation in ApoE -/- mice. Conclusions: RAP@T/R NPs hold a great promise as a drug delivery system for safer and more efficient therapy of atherosclerosis.

Fluid shear stress (FSS) facilitates bone remodeling by regulating osteogenic differentiation, and extracellular matrix maturation and mineralization. However, the underlying molecular mechanisms of how mechanical stimuli from FSS are converted into osteogenesis remain largely unexplored. Here, we exposed MC3T3-E1 cells to FSS with different intensities (1 h FSS with 0, 5, 10, and 20 dyn/cm2 intensities) and treatment durations (10 dyn/cm2 FSS with 0, 0.5, 1, 2 and 4 h treatment). The results demonstrate that the 1 h of 10 dyn/cm2 FSS treatment greatly upregulated the expression of osteogenic markers (Runx2, ALP, Col I), accompanied by AnxA6 activation. The genetic ablation of AnxA6 suppressed the autophagic process, demonstrating lowered autophagy markers (Beclin1, ATG5, ATG7, LC3) and decreased autophagosome formation, and strongly reduced osteogenic differentiation induced by FSS. Furthermore, the addition of autophagic activator rapamycin to AnxA6 knockdown cells stimulated autophagy process, and coincided with more expressions of osteogenic proteins ALP and Col I under both static and FSS conditions. In conclusion, the findings in this study reveal a hitherto unidentified relationship between FSS-induced osteogenic differentiation and autophagy, and point to AnxA6 as a key mediator of autophagy in response to FSS, which may provide a new target for the treatment of osteoporosis and other diseases.