Background: Gypenosides (Gyp) are the main ingredient of the Chinese medicine, Gynostemma pentaphyllum. They are widely used in Asia as a hepatoprotective agent. Here, we elucidated the mechanism of Gyp in non-alcoholic steatohepatitis (NASH) with a focus on farnesoid X receptor (FXR)-mediated bile acid and lipid metabolic pathways. Methods: NASH was induced in mice by high-fat diet (HFD) feeding, while mice in the control group were given a normal diet. At the end of week 10, HFD-fed mice were randomly divided into HFD, HFD plus Gyp, and HFD plus obeticholic acid (OCA, FXR agonist) groups and were given the corresponding treatments for 4 weeks. Next, we analyzed the histopathological changes as well as the liver triglyceride (TG) level and serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), fasting blood glucose (FBG), fasting insulin (FINS), TG, total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) levels as well as the bile acid profile. We carried out RT-PCR and western blotting to detect HFD-induced alterations in gene/protein expression related to bile acid and lipid metabolism. Results: The HFD group had histopathological signs of hepatic steatosis and vacuolar degeneration. The liver TG and serum ALT, AST, FBG, FINS, TC, and LDL-C levels as well as the total bile acid level were significantly higher in the HFD group than in the control group (P < 0.01). In addition, we observed significant changes in the expression of proteins involved in bile acid or lipid metabolism (P < 0.05). Upon treatment with Gyp or OCA, signs of hepatic steatosis and alterations in different biochemical parameters were significantly improved (P < 0.05). Further, HFD-induced alterations in the expression genes involved in bile acid and lipid metabolism, such as CYP7A1, BSEP, SREBP1, and FASN, were significantly alleviated. Conclusions: Gyp can improve liver lipid and bile acid metabolism in a mouse model of NASH, and these effects may be related to activation of the FXR signaling pathway.

T cell-based immunotherapies exhibit limited efficacy against solid tumors, a challenge primarily attributed to the immunosuppressive and mechanically hostile tumor microenvironment (TME). Within this context, the mechanosensitive ion channel Piezo1 has emerged as a key TME mechanosensor, yet its role in modulating T cell-mediated anti-tumor immunity remains to be fully elucidated. This review aims to synthesize existing evidence on Piezo1’s regulation of T cell functions, including activation, proliferation, and infiltration, and its broader impact on immunotherapy for solid tumors. We highlight Piezo1’s dual regulatory function in the immune landscape: acute activation robustly enhances T cell effector functions and cytotoxicity, whereas chronic stimulation within the stiff TME paradoxically promotes T cell exhaustion. Importantly, preclinical studies demonstrate that modulating Piezo1 signaling, particularly in combination with matrix normalization synergistically enhances the infiltration, persistence, and overall antitumor efficacy of adoptive T cells and endogenous immune responses. These findings position Piezo1 as a promising mechanical checkpoint for improving T cell therapies. Nevertheless, significant challenges persist for clinical implementation, including the heterogeneity of mechanical signals and the pleiotropic nature of Piezo1 across different cell types. Future research should therefore focus on developing T cell-specific mechanotherapies, identifying novel targets, and validating mechanical biomarkers to guide patient stratification, thereby accelerating the clinical translation of “mechanoimmunology”.

Natural Killer (NK) cells serve a critical function in antitumor immunity. However, their effectiveness is often hampered by the biomechanical properties of the solid tumor microenvironment (TME), such as the stiffness of the extracellular matrix. This review focuses on the mechanosensitive ion channel Piezo1 and its role in enhancing NK cell function. Studies have shown that tumor cell stiffness, as a key physical cue, directly influences the responsiveness of NK cells. In three-dimensional (3D) matrices, the stiffening of the extracellular matrix (ECM) can activate Piezo1, leading to calcium influx that substantially boosts NK cells’ cytotoxicity and tumor infiltration ability. Remarkably, similar to Yoda1, a specific Piezo1 agonist, short-term Piezo1 activation significantly enhances NK cells’ cytotoxicity and infiltration capacity. Whether such benefits persist under prolonged stimulation without inducing functional exhaustion remains to be determined. Unlike broader review articles that discuss TME biomechanics, this study focuses on uncovering the signal transduction mechanism of the Piezo1–NK cell axis, providing new perspectives and strategies for addressing immunotherapy resistance. This mechanobiology-based framework, through detailed analysis of the Piezo1-NK cell signaling transduction mechanism, is expected to overcome bottlenecks in NK cell immunotherapy. Its application prospects are not limited to the field of oncology but can also be extended to other diseases sensitive to mechanical signals.