Therapeutics targeting osteoclasts are commonly used treatments for bone metastasis; however, whether and how osteoclasts regulate premetastatic niche and bone tropism are largely unknown. In this study, we report that osteoclast precursors (OPs) can function as a premetastatic niche component that facilitates breast cancer (BCa) bone metastasis at early stages. At the molecular level, unbiased GPCR ligand/agonist screening in BCa cells suggested that R-spondin 2 (RSPO2) and RANKL, through interaction with their receptor LGR4, promoted osteoclastic premetastatic niche formation and enhanced BCa bone metastasis. This was achieved by RSPO2/RANKL-LGR4 signal modulating the WNT inhibitor DKK1 through Gα_q and β-catenin signaling. DKK1 directly facilitated OP recruitment through suppression of its receptor LDL receptor–related protein 5 (LRP5) but not LRP6, upregulating Rnasek expression via inhibition of canonical WNT signaling. In clinical samples, RSPO2, LGR4, and DKK1 expression showed a positive correlation with BCa bone metastasis. Furthermore, soluble LGR4 extracellular domain (ECD) protein, acting as a decoy receptor for RSPO2 and RANKL, significantly alleviated bone metastasis and osteolytic lesions in a mouse bone metastasis model. These findings provide unique insights into the functional role of OPs as key components of the premetastatic niche for BCa bone metastasis and identify RSPO2/RANKL-LGR4 signaling as a promising target for inhibiting BCa bone metastasis.

Cancers have been considered as one of the most severe health problems in the world. Efforts to elucidate the cancer progression reveal the importance of bone metastasis for tumor malignancy, one of the leading causes for high mortality rate. Multiple cancers develop bone metastasis, from which breast cancers exhibit the highest rate and have been well-recognized. Numerous cells and environmental factors have been believed to synergistically facilitate bone metastasis in breast cancers, from which breast cancer cells, osteoclasts, osteoblasts, and their produced cytokines have been well-recognized to form a vicious cycle that aggravates tumor malignancy. Except the cytokines or chemokines, calcium ions are another element largely released from bones during bone metastasis that leads to hypercalcemia, however, have not been well-characterized yet in modulation of bone metastasis. Calcium ions act as a type of unique second messenger that exhibits omnipotent functions in numerous cells, including tumor cells, osteoclasts, and osteoblasts. Calcium ions cannot be produced in the cells and are dynamically fluxed among extracellular calcium pools, intracellular calcium storages and cytosolic calcium signals, namely calcium homeostasis, raising a possibility that calcium ions released from bone during bone metastasis would further enhance bone metastasis and aggravate tumor progression via the vicious cycle due to abnormal calcium homeostasis in breast cancer cells, osteoclasts and osteoblasts. TRPs, VGCCs, SOCE, and P2Xs are four major calcium channels/routes mediating extracellular calcium entry and affect calcium homeostasis. Here we will summarize the overall functions of these four calcium channels in breast cancer cells, osteoclasts and osteoblasts, providing evidence of calcium homeostasis as a vicious cycle in modulation of bone metastasis in breast cancers.

Elucidating the temporal process of immune remodeling under immunosuppressive treatment after liver transplantation (LT) is critical for precise clinical management strategies. Here, we performed a single-cell multi-omics analysis of peripheral blood mononuclear cells (PBMCs) collected from LT patients (with and without acute cellular rejection [ACR]) at 13 time points. Validation was performed in two independent cohorts with additional LT patients and healthy controls. Our study revealed a four-phase recovery process after LT and delineated changes in immune cell composition, expression programs, and interactions along this process. The intensity of the immune response differs between the ACR and non-ACR patients. Notably, the newly identified inflamed NK cells, CD14⁺RNASE2⁺ monocytes, and FOS-expressing monocytes emerged as predictive indicators of ACR. This study illuminates the longitudinal evolution of the immune cell landscape under tacrolimus-based immunosuppressive treatment during LT recovery, providing a four-phase framework that aids the clinical management of LT patients.

Diabetic Mellitus (DM), a chronic metabolic disorder disease characterized by hyperglycemia, is mainly caused by the absolute or relative deficiency of insulin secretion or decreased insulin sensitivity in target tissue cells. Dihydromyricetin (DMY) is a flavonoid compound of dihydroflavonol that widely exists in Ampelopsis grossedentata. This review aims to summarize the research progress of DMY in the treatment of DM. A detailed summary of related signaling induced by DMY are discussed. Increasing evidence implicates that DMY display hypoglycemic effects in DM via improving glucose and lipid metabolism, attenuating inflammatory responses, and reducing oxidative stress, with the signal transduction pathways underlying the regulation of AMPK or mTOR/autophagy, and relevant downstream cascades, including PGC-1α/SIRT3, MEK/ERK, and PI3K/Akt signal pathways. Hence, the mechanisms underlying the therapeutic implications of DMY in DM are still obscure. In this review, following with a brief introduction of the absorption, metabolism, distribution, and excretion characteristics of DMY, we summarized the current pharmacological developments of DMY as well as possible molecular mechanisms in the treatment of DM, aiming to push the understanding about the protective role of DMY as well as its preclinical assessment of novel application.

Fibroblast collagen synthesis is a hallmark of the pathogenesis and progression of pulmonary fibrosis (PF). However, the factors that trigger the abnormal activation of fibroblasts in PF are still not well understood. Using proteomics and single‐cell sequencing dataset screening, extra accumulation of Cathepsin K (CTSK) is detected in the periphery as well as in fibroblasts in the lungs of PF mouse models. Addition of recombinant CTSK (rCTSK) aggravates collagen accumulation and PF progression in bleomycin‐induced PF mice. Mechanically, CTSK underwent endocytosis through interaction with sorting nexin 9 (SNX9), which is engaged in TGF‐β1 induced SMAD3 activation for downstream glutaminase 1 (GLS1) upregulation and glutamine enrichment. In turn, extra glutamine increases collagen synthesis in fibroblasts. More significantly, serum CTSK levels positively correlated with glutamine levels and poor prognosis in patients with PF. Thus, the results identify CTSK as a novel regulator of fibroblast activation that remodels glutamine metabolism and promotes collagen synthesis during PF pathogenesis. The correlation between peripheral CTSK and glutamine levels implies its future feasibility in the prediction and prevention of PF progression.