Piezo channels are mechanosensitive ion channels located in the cell membrane and function as key cellular mechanotransducers for converting mechanical stimuli into electrochemical signals. Emerged as key molecular detectors of mechanical forces, Piezo channels’ functions in bone have attracted more and more attention. Here, we summarize the current knowledge of Piezo channels and review the research advances of Piezo channels’ function in bone by highlighting Piezo1′s role in bone cells, including osteocyte, bone marrow mesenchymal stem cell (BM-MSC), osteoblast, osteoclast, and chondrocyte. Moreover, the role of Piezo channels in bone diseases is summarized.

Liquid–liquid phase separation (LLPS) compartmentalizes and concentrates biomacromolecules into liquid-like condensates, which underlies membraneless organelles (MLOs) formation in eukaryotic cells. With increasing evidence of the LLPS concept and methods, this phenomenon as a novel principle accounts for explaining the precise spatial and temporal regulation of cellular functions. Moreover, the phenomenon that LLPS tends to concentrate proteins is often accompanied by several abnormal signals for human diseases. It is reported that multiple metabolic diseases are strongly associated with the deposition of insoluble proteinaceous aggregating termed amyloids. At present, recent studies have observed the roles of LLPS in several metabolic diseases, including type 2 diabetes mellitus (T2DM), Alzheimer’s disease (AD), and metabolic bone diseases (MBDs). This review aims to expound on the current concept and methods of LLPS and summarize its vital roles in T2DM, AD, and MBDs, uncover novel mechanisms of these metabolic diseases, and thus provide powerful potential therapeutic strategies and targets for ameliorating these metabolic diseases.

Ferroptosis, a distinct form of programmed cell death characterized by iron-dependent lipid peroxidation, has emerged as a critical factor in the pathogenesis of various diseases. Given the increasing prevalence of osteoporosis worldwide and the increasing incidence of osteoporosis, understanding the molecular mechanisms underlying bone loss is imperative for developing targeted therapies. Recent evidence suggests that ferroptosis plays a pivotal role in osteoporosis by influencing the balance between osteoblast and osteoclast activity. This review examines the mechanistic basis of ferroptosis and its pathological implications in osteoporosis. By delineating the interplay between ferroptosis and skeletal remodeling, we highlight potential therapeutic strategies aimed at modulating ferroptosis to mitigate osteoporosis progression.

Decreased osteoblast differentiation contributes to bone loss induced by mechanical unloading. However, the underlying mechanism is still unclear. We previously found that microtubule actin crosslinking factor 1 (MACF1), a key cytoskeletal protein, plays an important role in regulating osteoblast differentiation, while the role of MACF1 in mechanical unloading suppressing osteoblast differentiation remains unclear. Here, an MACF1-knockdown (MACF1-KD) osteoblast cell line and primary osteoblasts were subjected to mechanical unloading conducted by a random positioning machine (RPM). Osteoblast differentiation was evaluated by alkaline phosphatase (ALP) staining and real-time PCR. F-actin distribution was examined by immunofluorescence staining. Western blot was adopted to detect the protein levels. Moreover, cytochalasin B and PD98059 were applied to disrupt F-actin and inhibit extracellular signal-regulated kinase (ERK) activity, respectively, to confirm the mechanism. The results show that MACF1 is significantly downregulated in osteoblasts by mechanical unloading together with decreased osteoblast differentiation. MACF1-KD osteoblasts exhibit reduced differentiation capacity and are insensitive to mechanical unloading. Mechanistically, MACF1 mediates the suppression of mechanical unloading on osteoblast differentiation by regulating F-actin distribution and the downstream ERK/Runx2 signaling. Furthermore, F-actin disruption and ERK inhibition assays confirm that MACF1 mediates the impairment of mechanical unloading on osteoblast differentiation via the F-actin/ERK/Runx2 axis. In conclusion, this study reveals MACF1 as a mechanotransduction mediator for mechanical unloading, inhibiting osteoblast differentiation via F-actin/ERK/Runx2, and contributes to a novel mechanistic insight of cell mechanotransduction.

The progression of skeletal senescence under mechanical unloading conditions elevates fracture risk, emerging as a critical health challenge for the general population and astronauts during spaceflight. Nevertheless, current therapeutic strategies demonstrate persistent limitations in efficacy and safety, with unresolved challenges in long-term sustainability. Baicalein, a natural flavonoid compound, exhibits favorable anti-aging and anti-inflammatory effects, while its therapeutic potential and underlying mechanism in bone disorders remain unknown. In this study, a hind limb unloading (HLU) rat model was employed as a disuse simulation, after which the HLU rats received baicalein treatment by gavage at 30 mg·kg⁻¹·day⁻¹ for 4 weeks. Our results show that baicalein mitigates disuse-driven skeletal aging by ameliorating trabecular microstructure (Tb. N increased by 38.04%), accelerating bone mineral apposition rate (MAR increased by 42.76%), increasing bone mineral density (1.20-fold vs. model group), improving biomechanical strength (ultimate load +31.64%) and downregulating senescence-associated markers p16, p21, p53 in tibial tissue. Additionally, baicalein alleviated the unloading-induced high bone turnover, as evidenced by reducing serum levels of both osteogenic biomarkers ALP, PINP, BGP and osteoclastic biomarkers TRACP 5b, RANKL, NTX. Moreover, baicalein suppressed the inflammatory response caused by mechanical unloading, attributed to the restriction of pro-inflammatory factors TNF-α, IL-6, IL-8, IFN-γ and the promotion of anti-inflammatory cytokines IL-4, IL-10. Importantly, baicalein ameliorated the unloading-induced gut microbiota disorder through the diminished abundance of Proteobacteria and elevated abundance of Actinobacteria and Firmicutes, which were negatively associated with inflammatory response. Overall, our study provides evidence that baicalein inhibits the inflammatory response through the regulation of gut microbiota balance, which plays a role in preserving bone homeostasis.

With the rapid expansion of terahertz (THz) technologies across communications, imaging, sensing, and biomedicine, defining their biological effects, safety boundaries, and controlled intervention has become a critical scientific priority for their responsible deployment. Although diverse biological responses have been observed at different levels of biological organization, the findings are highly dependent on exposure parameters and biological models. Moreover, how molecular perturbations propagate across scales to produce higher-order biological effects remains poorly understood. Because biomacromolecules and their hydration environments constitute the primary interface which THz radiation interacts with biological systems, elucidating THz bioeffects at the molecular scale is essential for mechanistic understanding. Here, we systematically review recent advances in THz interactions with key biological targets, including proteins, nucleic acids, ion channels, and biological membranes, and examine how local molecular perturbations translate into higher-level phenotypes. On this basis, we critically assess the major challenges facing the field and propose an integrative framework for mechanistic validation. By consolidating dispersed findings and emphasizing methodological standardization, this review provides a coherent conceptual basis for interpreting THz bioeffects and guiding their biomedical translation.