International Journal of Biological Sciences最新文献

Radioresistance remains a critical barrier to successful radiotherapy in non-small cell lung cancer (NSCLC). ATMLP, a mitochondrial-localized peptide encoded by lncRNA AFAP1-AS1, has been previously associated with tumor progression. In this study, we uncover a previously unrecognized role of ATMLP in promoting radioresistance by facilitating intracellular lipid droplet (LD) accumulation through AKT pathway activation. Mechanistically, ATMLP reduces radiation-induced reactive oxygen species (ROS) accumulation, thereby relieving ROS-mediated suppression of AKT phosphorylation, which in turn enhances lipid storage and promotes tumor cell survival under ionizing radiation. Genetic knockout of ATMLP leads to excessive ROS generation, impaired AKT activation, and diminished LD accumulation, ultimately sensitizing NSCLC cells to radiation. Conversely, ATMLP overexpression decreases ROS levels, increases post-radiation clonogenicity, and accelerates tumor growth. Inhibition of the AKT pathway abrogates ATMLP-induced lipid accumulation and reverses the radioresistant phenotype. These findings identify ATMLP as a key mediator linking ROS homeostasis and lipid metabolic reprogramming to radiation response, and suggest that targeting the ATMLP-AKT axis may represent a promising therapeutic strategy to enhance radiotherapy efficacy in NSCLC.

Induction of pyroptosis is considered as a novel strategy for the treatment of multiple myeloma, but the potential targets remain unknown. In the present study, we found that GSDME, a key executor of pyroptosis, is the mostly downregulated pyroptosis-related gene in MM cells and its low expression predicts poor prognosis of MM patients. Out of expectation, GSDME transcription is not markedly affected by epigenetic manners in MM cells. In contrast, GSDME expression is controlled by the transcription factor FOXO3. FOXO3 binds to the two recognition sites and upregulates GSDME. Moreover, FOXO3 specifically upregulates the BNIPL family proteins and activates Caspase-3 and GSDME therefore triggering MM cell pyroptosis. In addition, similar to GSDME, FOXO3 is also downregulated in MM and its restoration suppresses myeloma tumor growth. Furthermore, we found corylin, a flavonoid derived from Psoralea Fructus, activates the transcription of both FOXO3 and GSDME. As expected, corylin displays potent anti-MM activity in association with pyroptosis by upregulating FOXO3 and GSDME. In conclusion, FOXO3 is a novel transcription factor of GSDME. Restoration/activation of the FOXO3/GSDME axis could be a promising novel strategy for the treatment of MM.

The progression and therapeutic response of clear cell renal cell carcinoma (ccRCC) are critically shaped by the complex interactions between tumor cell heterogeneity and the tumor immune microenvironment (TIME). However, a comprehensive classification of the ccRCC ecosystem and its clinical relevance is lacking. To address this, we utilized comprehensive bioinformatics approaches to analyze ten public single-cell RNA sequencing datasets from 194 samples across 118 ccRCC patients. Across 1,172,154 cells, we identified four TIME subtypes (immune activation, innate immunity, immunosuppressive myeloid [ISM], and immune exclusion) and six functional states of tumor cells (metabolic, angiogenic, stress-responsive, antigen-presenting, cell cycling, and epithelial-mesenchymal transition [EMT]). The interplay between these components defined four immune ecosystems, among which the ISM subtype, coupled with the EMT tumor state was associated with the poorest prognosis. Using machine learning-based prognostic modeling, we highlighted FKBP10 as a critical prognostic gene. Mechanistically, we demonstrated that FKBP10 not only promoted EMT but also activated the MEK/ERK/ELF3 signaling axis, leading to an increased secretion of CXCL8 by tumor cells. Tumor-derived CXCL8, in turn, drove macrophage M2 polarization and myeloid-derived suppressor cell (MDSC) recruitment, thereby reinforcing an immunosuppressive TIME. Furthermore, targeting FKBP10 synergized with anti-PD-1 therapy in suppressing tumor growth in vivo. Our work provides a comprehensive molecular atlas of the ccRCC ecosystem, establishes FKBP10 as a key regulator of immune suppression, and highlights its potential as a therapeutic target for personalized immunotherapy.

Neuronal ferroptosis is considered as a key mechanism contributing to neurological deficits during the secondary injury phase following spinal cord injury (SCI). Clusterin (CLU), a stress-responsive protein, has been reported to exert neuroprotective effects and promote neuronal survival in central nervous system injuries. However, its specific role in neuronal ferroptosis remains unclear. Here, we demonstrate that both exogenous recombinant CLU protein and endogenous CLU overexpression significantly inhibit neuronal ferroptosis, as evidenced by reduced lipid peroxidation, decreased iron accumulation, preserved mitochondrial integrity, and modulation of ferroptosis-related genes (upregulation of GPX4/xCT and downregulation of ACSL4). Mechanistically, CLU activates the PI3K-AKT-mTOR pathway, subsequently regulating the SREBP1-SCD1 lipid metabolism axis to suppress ACSL4-mediated lipid peroxidation. Furthermore, AAV-mediated CLU overexpression effectively mitigates pathological damage and significantly enhances motor function recovery in SCI mice. In conclusion, this study reveals a novel mechanism whereby CLU promotes SCI repair by inhibiting neuronal ferroptosis via the PI3K-AKT-mTOR-SREBP1 axis, indicating its therapeutic potential for ferroptosis-targeted neuroprotective strategies.

Radioiodine (RAI) therapy, used for treating differentiated thyroid cancers (DTCs), hinges on the functional expression of the sodium-iodide symporter (NIS). However, up to 60% of papillary thyroid carcinomas, the most common DTC subtype, harbor BRAF^V600E mutations, which are strongly associated with reduced NIS expression, impaired RAI uptake, and poor differentiation scores. For patients with RAI-refractory, a promising therapeutic strategy is to restore RAI sensitivity by inducing tumor redifferentiation. Here, we demonstrate that NOX4-derived reactive oxygen species (ROS) contribute to NIS repression in BRAF^V600E-mutated thyroid cancer cells. Particularly, NOX4-generated oxidative DNA damage recruits DNA repair proteins, including OGG1 and MSH2/MSH6 proteins, which in cooperation with DNMT1, convert these lesions into transcription-blocking events. This mechanism prevents key thyroid differentiation transcription factors, PAX8 and NKX2.1, from accessing their chromatin binding sites, thereby silencing NIS expression. Importantly, combining inhibition of the MAPK pathway, which regulates MSH2/MSH6 and DNMT1 expression, and the TGF-β1 pathway, which controls NOX4 expression, restores PAX8 and NKX2.1 chromatin occupancy. Compared to normal tissue an increased expression of NOX4, OGG1, MSH2/MSH6 proteins and phospho-Smad3 was found in RAI Refractory BRAF^V600E mutated tumors. Collectively, our findings reveal a mechanistic basis for NOX4's role in thyroid dedifferentiation.

Research on cholesterol and its metabolic pathways has catalyzed the development of anticancer drugs targeting cholesterol synthesis. However, the cholesterol metabolic state in melanoma remains poorly characterized. In this study, we found that total cholesterol levels and the expression of acetyl-CoA acetyltransferase 2 (ACAT2), a key cholesterogenic enzyme, were significantly elevated in melanoma cells. ACAT2-mediated de novo cholesterol synthesis promoted melanoma growth both in vitro and in vivo. Furthermore, we identified that the transcription factor SOX10, which is critical for melanocyte development, was specifically highly expressed in melanoma and directly upregulated ACAT2 expression, thereby promoting cholesterol synthesis and tumor proliferation. Mechanistically, SOX10 transcriptionally activated ACAT2 expression by interacting with TAF15. This SOX10-TAF15 complex subsequently enhanced ACAT2 protein levels, stimulated cholesterol synthesis, suppressed apoptosis, and ultimately drove melanoma proliferation. Our findings reveal that the SOX10-TAF15-ACAT2 axis is a key regulator of cholesterol synthesis and melanoma proliferation, presenting a promising therapeutic target.

Mechanical overload is closely associated with the theory of uneven tibial plateau settlement in knee osteoarthritis (KOA). Excessive mechanical stress leads to abnormal force distribution within the subchondral bone, eventually inducing medial tibial plateau collapse. This process disrupts local biomechanical homeostasis and triggers aberrant bone remodeling. However, the precise molecular basis of subchondral bone remodeling and structural changes in the knee is still not fully understood. In this work, we employed a mouse model of KOA with osteoblast-specific Piezo1 deletion, together with in vitro loading experiments, to demonstrate that mechanical overload activates Piezo1, promotes Ca²⁺ influx, and drives osteoblast differentiation, thereby contributing to subchondral bone sclerosis. Mechanistic investigations revealed that inhibition of the Piezo1-JAK2/STAT3 signaling axis alleviated abnormal osteoblast activation and significantly ameliorated subchondral bone sclerosis and cartilage degeneration. Moreover, deletion of JAK2 in osteoblasts further confirmed that blockade of this pathway mitigates KOA progression in vivo. Collectively, our findings identify the Piezo1-Ca²⁺-JAK2/STAT3 axis as a key mediator of osteoblast mechanotransduction under pathological loading and a potential therapeutic target for mechanical overload-associated KOA.

Vandetanib, a critical therapy for advanced thyroid and RET-driven cancers, is limited by life-threatening hepato-cardiotoxicity. This study identifies lysosomal protease cathepsin B (CTSB) as the central mediator of vandetanib-induced organ damage through STAT3-driven transcriptional activation. CTSB triggers mitochondrial apoptosis by cleaving the lysosomal calcium channel mucolipin TRP cation channel 1 (MCOLN1), disrupting calcium/AMP-activated protein kinase (AMPK) signaling and autophagy flux. Crucially, the natural compound tannic acid directly binds and inhibits CTSB, completely protecting against hepato-cardiotoxicity without compromising vandetanib's antitumor efficacy in preclinical models. Overall, our findings establish CTSB-mediated lysosomal dysfunction and MCOLN1-calcium-AMPK axis disruption as the core mechanism of vandetanib-induced hepato-cardiotoxicity, and identify tannic acid as a readily translatable adjuvant strategy to prevent this toxicity. These findings redefine CTSB as a druggable target for kinase inhibitor toxicities and position tannic acid as a clinically translatable adjuvant to enhance vandetanib's safety profile. By preserving lysosomal function and calcium homeostasis, this strategy addresses a critical unmet need in precision oncology, enabling prolonged, safer use of vandetanib and related tyrosine kinase inhibitors. The discovery of shared lysosomal injury mechanisms across organs also opens avenues for preventing multi-organ toxicities in broader cancer therapies.

Cancer is a leading cause of death in Western countries. Apart from surgical resection, the primary treatment modalities chemotherapy and radiotherapy inflict serious side effects, and significantly remodel both tumor metabolism and the tumor microenvironment. This consequently compromises treatment efficacy, resulting in multiple drug resistance, immune evasion and cancer progression. Lysosomes are unique acidic intracellular organelles crucial for maintaining cellular health and homeostasis via degradation of cellular waste. Lysosomes are also required for autophagy, a stress-induced catabolic pathway that is important for cell survival. Autophagy is typically enhanced in tumor cells, as it can confer cyto-protection against the deleterious cytotoxic effects of chemotherapy, and suppress anti-cancer immune response. Owing to their acidic nature and their role in endocytosis, lysosomes can be readily targeted and manipulated, thus attenuating the autophagic flux and improving cancer treatment outcome. Herein we focused on various classic and innovative lysosome modulators, their impact on autophagy, the enhancement of immune response, and consequent inhibition of tumor growth and metastasis. We discuss modalities to minimize adverse effects in cancer patients by either utilizing harmless compounds, achieving synergistic activity with combination therapies, or specifically targeting the tumor by using advanced nanoparticle technologies.

Background: Persistently elevated glycolysis is increasingly recognized as a driving force in diabetic kidney disease (DKD). As a product of glycolysis, lactate can induce histone lactylation, an emerging epigenetic mechanism associated with post-transcriptional modification. However, the molecular mechanism and clinical impact of histone lactylation in DKD remain largely understood. Methods and Results: Spatial transcriptomics analysis revealed upregulation of glycolytic genes in tubular epithelial cells (TECs), thus leading to elevated levels of renal lactate accumulation. PKM2 deficiency lowered the lactate production during the fibrotic process and decreased histone lactylation. Mechanistically, ChIP-seq & RNA-seq results showed lactate promoted histone H4 lysine 12 lactylation (H4K12la), which in turn enhanced RUNX1 transcription. RUNX1 subsequently activated HK1 and SLC2A1, which accelerated glycolysis and renal fibrosis of DKD. Further, SIRT3 expression was significantly decreased in the renal tubular cells in DKD. Furthermore, insufficient SIRT3 is functionally promote renal fibrosis by directly deacetylating RUNX1 at H4K12, leading to attenuated glycolytic process, and subsequently robust glycolytic ability and increased production of lactate. Conclusion: Thus, the study links RUNX1-mediated glycolysis to SIRT3-mediated histonelactylation epigenetic reprogramming in promoting the fibrotic process, providing better understanding of epigenetic regulation of DKD pathogenesis, and new therapeutic strategy for DKD.