Cells and tissues are continuously exposed to mechanical cues from their surrounding microenvironment. Mechanobiology investigates how these cues are converted into intracellular biochemical and transcriptional responses. Piezo1, a mechanosensitive cation channel, mediates Ca2+ influx in response to changes in cell membrane tension. This Ca2⁺ signal can influence the activity and subcellular localization of Yes-associated protein (YAP) in a context-dependent manner, thereby contributing to physiological homeostasis and pathological progression. This review specifically focuses on the role of the Piezo1/YAP axis in regulating key physiological processes such as skeletal development, neural plasticity, macrophage polarization, epithelial homeostasis and barrier function, and cardiac development. Under pathological conditions, aberrant mechanical cues such as disturbed shear stress, matrix stiffening, and sustained mechanical overload can activate Piezo1-mediated Ca2⁺ influx and YAP-dependent transcriptional programs, thereby promoting endothelial inflammation, vascular remodeling, tumor cell proliferation, epithelial-mesenchymal transition, metastasis, and degenerative changes in skeletal tissues. Furthermore, this review evaluates emerging intervention strategies targeting the Piezo1/YAP axis, including small-molecule modulators and nanotechnology-based approaches. Although these strategies have shown promise in preclinical studies, their clinical translation remains at an early stage and is limited by challenges related to target specificity, bioavailability, tissue-selective delivery, dosage control, off-target mechanobiological effects, and long-term safety. Overall, this review aims to elucidate the current understanding of the Piezo1/YAP axis from mechanistic insights to therapeutic perspectives, while highlighting the need for further validation before clinical application.
Rui-Ming Wen, Hai-Xia Wang, Weifeng Pan et al.· Biochemical Pharmacology· 0 citations
The malignant progression of cancer depends not only on oncogenic driver mutations but also on the adaptive rewiring of organelle stress responses that sustain cell survival under hostile tumor microenvironment (TME) conditions. Among these, the hijacking of lysosomal homeostasis has emerged as a critical vulnerability and a driver of therapeutic resistance. Glycoprotein nonmetastatic B (GPNMB), a highly glycosylated type I transmembrane protein predominantly localized to lysosomes, is robustly upregulated across multiple cancer types as an adaptive responder to lysosomal stress. In tumors, GPNMB drives proliferation, metastasis, and immune evasion by engaging multiple oncogenic signaling cascades, while simultaneously shaping an immunosuppressive TME through CD8+ T cell exhaustion and cytokine networks. Clinically, high GPNMB expression correlates with poor prognosis in breast cancer, hepatocellular carcinoma (HCC), lung cancer, glioblastoma (GBM), gastric cancer (GC), and osteosarcoma (OS), positioning it as both a prognostic biomarker and a therapeutic target. The GPNMB-directed antibody-drug conjugate (ADC) glembatumumab vedotin (GV) has demonstrated clinical activity in triple-negative breast cancer (TNBC) and melanoma, yet its efficacy remains constrained by target expression heterogeneity, the reliance on lysosomal trafficking for payload release, and dose-limiting toxicities. Emerging strategies, including bispecific antibodies, immunotoxins, and senolytic elimination of GPNMB-high damaged cells, are expanding the therapeutic landscape. This review dissects the molecular mechanisms, pathological roles, and evolving clinical applications of GPNMB in cancer, highlighting current challenges and future directions for precision oncology.
Hai-Xia Wang, Rui-Ming Wen, Zhongwei Yang et al.· Biochemical Pharmacology· 0 citations
The objective is to elucidate the context-dependent roles of TREM2 by analyzing consensus mechanisms, sources of discrepancy, and translational implications, thereby providing a theoretical framework and strategic direction for more precise TREM2-targeted interventions.
Hai-Xia Wang, Rui-Ming Wen, Emily Parker et al.· Cell communication and signa...· 0 citations
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