International Journal of Biological Sciences最新文献

Disuse osteoporosis (DOP), a skeletal disorder triggered by insufficient mechanical loading, manifests as progressive bone mass deterioration and microarchitectural weakening. Piezo1, a key mechanosensitive ion channel expressed in bone cells, is implicated in maintaining skeletal homeostasis. Using a murine hindlimb unloading (HLU) model simulating microgravity-induced bone loss, we observed significant downregulation of Piezo1 expression in bone tissue and isolated bone marrow-derived mesenchymal stem cells (BMSCs). Systemic administration of the Piezo1 agonist Yoda1 attenuated HLU-induced osteopenia and improved bone formation capacity. Mechanistic studies in BMSCs demonstrated that Piezo1 activation promoted mitochondrial biogenesis. This effect required AMPK/SIRT1 signaling-dependent deacetylation of PGC-1α, leading to enhanced mitochondrial function, improved osteogenic differentiation, and reduced apoptosis. Critically, pharmacologic inhibition of SIRT1 abolished the osteoprotective effects of Yoda1 in vivo. These findings establish that mechanical unloading impairs Piezo1-mediated mechanotransduction in BMSCs, contributing to disrupted skeletal homeostasis, which can be mitigated by exogenous Piezo1 activation. Our results define a mechanism where Piezo1 integrates mechanical signals into the AMPK/SIRT1/PGC-1α signaling cascade to regulate mechanoadaptive bone formation, highlighting Piezo1 activation as a potential mechanism-based therapeutic strategy for disuse osteoporosis.

Lung cancer (LC), prostate cancer (PC), and breast cancer (BC) are the three most prevalent cancers that lead to bone metastasis (BoM). In this study, we conducted an integrated analysis of single-cell transcriptomic data from the primary tumors and BoM across PC, LC, and BC. We discover a novel subtype of tumor-associated macrophages (TAMs) that are positive both for matrix metalloproteinase 19 (MMP19) and receptor activator of nuclear factor-κB (RANK) expression (MMP19⁺ RANK⁺ TAMs). MMP19⁺ RANK⁺ TAMs demonstrate an increased level of M2 polarization and act as a critical driving factor for LC-BoM. MMP19⁺ RANK⁺ TAMs are organized in a ring-like arrangement surrounding the tumor nests, constructing a barrier structure that impedes the infiltration of CD8⁺ T cells into the tumor core in LC-BoM. RANKL inhibitor Denosumab has been shown to effectively reduce the level of M2 polarization, decrease the population of MMP19⁺ RANK⁺ TAMs, and disrupt their barrier structure. Denosumab facilitates the infiltration of CD8⁺ T cells into the interior of LC-BoM tissues. Based on this mechanism, we observed in both clinical cohorts and preclinical models that RANKL inhibitor can enhance the efficacy of immunotherapy in treating LC-BoM.

Renal allograft interstitial fibrosis, a key pathological feature of chronic renal allograft dysfunction (CAD), is a critical determinant of long-term graft survival. However, its underlying molecular mechanisms remain incompletely understood. This study uncovers the central role of programmed cell death, particularly the novel PANoptosis modality, in the progression of CAD. PANoptosis integrates features of pyroptosis, apoptosis, and necroptosis, but does not fit within the confines of any single pathway, with its mechanisms previously undefined. By analyzing cell death patterns in CAD tissues through single-cell sequencing and validating findings via in vivo and in vitro experiments, this work demonstrates that in the context of chronic inflammation, tumor necrosis factor-alpha (TNF-α) modulates signal transducer and activator of transcription 1 (STAT1) through dual phosphorylation. This process directly induces tyrosine 701 phosphorylation and activates serine 727 phosphorylation via the p38 MAPK pathway. Phosphorylated STAT1 subsequently upregulates the PANoptosome sensor absent in melanoma 2 (AIM2), driving PANoptosis in renal tubular epithelial cells. This mechanism further exacerbates interstitial fibrosis by promoting the paracrine secretion of interleukin-6 and transforming growth factor-beta, which induces epithelial-mesenchymal transition (EMT) in adjacent tubular cells. These findings represent the first demonstration of the TNF-α/STAT1/AIM2 axis in triggering PANoptosis and its downstream EMT-fibrosis cascade, offering novel therapeutic targets for CAD intervention.

Although essential for normal development and tissue homeostasis, aberrant activation of the Hedgehog (Hh) signaling pathway is implicated in non-small cell lung cancer (NSCLC) progression and treatment resistance. This review details the contribution of Hh signaling to NSCLC, focusing on its promotion of tumor invasion and therapeutic resistance, and establishes a rationale for disrupting this pathway to improve treatment efficacy. Malignant phenotypes in NSCLC are driven by dysregulated Hh pathway activity, often via autocrine or paracrine loops. We specifically assess how Hh pathway activation enables tumor invasion, metastasis, and the development of drug resistance. The review elucidates key resistance mechanisms against diverse therapies-encompassing chemotherapy, targeted therapy and immunotherapy-with a focus on epithelial-mesenchymal transition (EMT), cancer stem cell maintenance, and multidrug resistance (MDR). Therefore, combining Hh pathway inhibitors with standard therapies represents a promising approach for managing treatment-resistant NSCLC.

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality, highlighting the need for a deeper understanding of its molecular mechanisms to drive the development of novel therapeutic approaches. In this study, the findings indicated a significant reduction in PDZ Domain Containing Family Member 1 (GIPC1) expression in CRC tissues, which correlated with poor prognosis in patients with CRC at pathological stages T1 and T2. GIPC1 acted as a tumor suppressor gene that inhibited CRC cell proliferation, colony formation, migration, and invasion. Additionally, it enhanced CRC cell sensitivity to first-line chemotherapies such as 5-fluorouracil (5-FU), oxaliplatin (OXA), and irinotecan (CPT-11). Mechanistically, GIPC1 reduced the ubiquitination level of tetratricopeptide repeat domain 7B (TTC7B) by downregulating the E3 ubiquitin ligase TRIM21, thereby stabilizing TTC7B's expression and inhibiting the downstream mTOR/NF-κB signaling cascade. Moreover, in vivo studies confirmed the inhibitory role of GIPC1 in CRC growth and found that GIPC1-loaded lipid nanoparticles (GIPC1-LNPs) combined with 5-FU treatment had a more significant antitumor effect. In conclusion, this study reveals the GIPC1/TRIM21/TTC7B/mTOR/NF-κB tumor-suppressive axis in CRC and highlights the potential of GIPC1 for early diagnosis and overcoming chemoresistance in CRC patients.

While cisplatin-based chemoradiotherapy regimens (gemcitabine-cisplatin [GP] and docetaxel-cisplatin-5-fluorouracil [TPF]) remain standard treatments for advanced nasopharyngeal carcinoma (NPC), 30-40% of patients exhibit intrinsic chemoresistance, resulting in therapeutic failure. The molecular underpinnings of this resistance are poorly characterized. Through integrative multi-omics profiling, we identified Mitochondrial Ribosomal Protein S7 (MRPS7) and Mitochondrial Ribosomal Protein S23 (MRPS23) as novel drivers of cisplatin resistance in NPC. Mechanistically, integrated single-cell RNA-seq (scRNA-seq) analysis, mass spectrometry, and functional studies revealed that MRPS7 and MRPS23 stabilized β-catenin by inhibiting its ubiquitination, thereby promoting β-catenin-mediated cancer stemness and epithelial-mesenchymal transition (EMT) to establish cisplatin resistance in NPC. Additionally, we identified Ubiquitin Specific Peptidase 10 (USP10) as a critical upstream regulator that protects MRPS7/23 from proteasomal degradation and sustaining their oncogenic activity. Notably, Spautin-1, a potent USP10 inhibitor, demonstrates synergistic therapeutic activity with cisplatin in diminished tumor growth and metastasis in NPC mice. This research established the USP10-MRPS7/MRPS23-β-catenin axis as a promising precision medicine strategy to combat metastatic dissemination and reverse cisplatin chemoresistance in advanced NPC, which offers a promising opportunity to develop cisplatin sensitizers for the clinical translation of NPC therapies.

One of the most important changes in the transformation of normal cells into tumor cells is metabolism. In order to satisfy the more active proliferation, migration and metastasis of cancer cells, abnormal changes occur in various pathways and molecules involved in metabolism, which eventually lead to metabolic reprogramming of tumor cells. This process involves the uptake of nutrients and changes in major metabolic forms. As an important part of post-transcriptional epigenetics, RNA methylation modifications can regulate RNA processing and metabolism, while dynamically and reversibly influencing the expression of specific molecules, thereby ultimately affecting diverse biological processes and cellular phenotypes. In this review, various types of RNA methylation modifications involved in cancer are summarized. Subsequently, we systematically elucidate the mechanism of RNA modification for metabolic reprogramming in cancer, including glucose, lipid, amino acid and mitochondrial metabolism. Most importantly, we discuss in depth the clinical significance of RNA modification in metabolic targeted therapy and immunotherapy from mechanism to therapeutic application.

Thyroid cancer is the most common endocrine malignancy globally. While papillary thyroid carcinoma (PTC) typically exhibits favorable prognosis, a subset undergoes dedifferentiation into anaplastic thyroid carcinoma (ATC), an aggressive, treatment-refractory subtype with near-universal lethality. However, the molecular driver of this process remains elusive. In this study, we find that IGF2BP2 is upregulated in ATC and correlates with adverse prognosis. Pseudotime trajectory analysis tracks progressively escalating IGF2BP2 expression throughout dedifferentiation. Functionally, IGF2BP2 promotes proliferation, suppresses thyroid differentiation genes (TSHR, SLC26A4, SLC5A5, TPO, PAX8, FOXE1, and NKX2.1), and enhances cancer stemness. Mechanistically, integrated multi-omics analysis (RNA-seq, RIP-seq, and MeRIP-seq) reveals that IGF2BP2 binds m6A-modified STAT1 mRNA, accelerating its decay. STAT1 directly activates transcription of thyroid differentiation genes. Rescue experiments confirms that STAT1 mediates IGF2BP2-driven dedifferentiation. The IGF2BP2-m6A-STAT1 complex is a master regulator of thyroid cancer dedifferentiation, establishing a novel therapeutic target for redifferentiation therapy in advanced thyroid cancer.

Arachidonic acid (AA)-derived lipid mediators play pivotal roles in inflammation and its resolution. While glycolysis is a key metabolic pathway determining macrophage polarization, the crosstalk between specific AA metabolites and glycolytic reprogramming remains poorly understood. In this study, we explore whether certain AA metabolites modulate macrophage function through covalent protein modification, with therapeutic implications for myocardial ischemia-reperfusion injury. Unlike conventional specialized pro-resolving mediators (SPMs) that primarily act via receptors, here we identify an endogenous electrophilic AA metabolite, 15-keto-prostaglandin F2α (15KPF), that covalently modifies pyruvate kinase M2 (PKM2) at Cys49. Such interaction enhanced PKM2 tetramerization, suppressed the PKM2/HIF-1α/STAT3 axis, redirected energy metabolism from glycolysis to mitochondrial respiration, and promoted pro-resolving M2 macrophage polarization. Mutated PKM2(C49S) failed to inhibit STAT3 signaling and blocked the effect of 15KPF on M1 to M2 phenotype switch. Moreover, 15KPF reduced infarct size and preserved myocardial integrity in in vivo model. Taken together, covalent 15-keto-PGF2α-PKM2 conjugation represents a self-regulatory mechanism linking AA metabolism to glycolysis to drive macrophage metabolic-inflammatory reprogramming. This pathway positions 15KPF as a promising therapeutic candidate for inflammatory and metabolic diseases, including ischemia-reperfusion injury, and distinguishes it from synthetic allosteric PKM2 activators such as TEPP-46.

Cholestatic liver injury (CLI) is a rapid progressive liver disorder characterized by the accumulation of bile acids (BA). Although pregnane X receptor (PXR) is a critical regulator of BA metabolism, the synergistic mechanisms of natural compounds targeting these pathways remain unclear. In this study, we demonstrated a positive correlation between BA accumulation and disease severity in clinical samples. Further, we identified Schisandrin B (Sin B), a lignan from Schisandra chinensis, as a potent hepatoprotective agent in α-naphthyl isothiocyanate (ANIT)- induced CLI. We demonstrated that Sin B treatment reduced BA levels and inflammation in ANIT-induced WRL68 cells, liver lobule chips, and mice. Notably, Sin B activated PXR, increased the levels of UDP-glucuronosyltransferase 1A1 (UGT1A1), CYP3A4 (in humans) / CYP3A11 (in mice) and MRPs, and enhanced TFEB transcriptional activity and autophagic flux in vivo and in vitro. Knockout of hepatic Pxr or Tfeb blocked these effects of Sin B. Mechanistic investigation revealed that Sin B is directly binds to PXR at residues S106, G144, and W299, inducing conformational changes in the ligand-binding domain (LBD) was verified through target fishing, molecular dynamics (MD) simulations, drug affinity responsive target stability assay, isothermal titration calorimetry and surface plasmon resonance. Our findings provide structural and functional insights into the dual-pathway mechanism of Sin B and support its therapeutic potential for CLI.