Inflammation is a prominent feature of the bone marrow microenvironment in acute myeloid leukemia and contributes to leukemic evolution, progression, and therapeutic resistance. Accumulating evidence indicates that inflammatory signals in AML arise from multiple sources, including age-associated inflammaging, mutation-driven pathways, cell-intrinsic stress programs, and external inflammatory stimuli such as infections. These signals collectively facilitate the progression from clonal hematopoiesis and other pre-leukemic states to overt leukemia and support malignant expansion. Leukemic blasts, immune effector and regulatory cells, mesenchymal stromal cells, and endothelial cells collectively establish an inflammatory niche through the production of cytokines and chemokines. This niche supports leukemic stem cell maintenance and fitness, promotes metabolic adaptation and survival, and disrupts normal hematopoiesis and immune surveillance. The inflammatory microenvironment can also compromise therapeutic efficacy by inducing drug tolerance, reinforcing protective bone marrow niches, and reshaping responses to chemotherapy, targeted therapies, immunotherapies, and transplantation-associated graft-versus-leukemia effects. Although increasing mechanistic insights have inspired strategies aimed at neutralizing inflammatory mediators, blocking downstream signaling pathways, or reprogramming the microenvironment to restore anti-leukemic immunity, such anti-inflammatory approaches remain incompletely explored in clinical practice. A deeper understanding of cell type-specific inflammatory circuits and cytokine interactions will be essential for developing rational combination therapies to overcome microenvironment-driven resistance.
Ribosome, the universally conserved cellular machinery, orchestrates protein synthesis across all organisms. Ribosome-associated factors that regulate translation during biogenesis and stress adaptation remain underexplored in archaea due to limited structural data. Here we present eight cryogenic electron microscopy (cryo-EM) structures of the archaeal 50S ribosomal subunit at resolutions of 2.07–3.26 Å, revealing a previously uncharacterized cystathionine β-synthase (CBS) domain-containing protein positioned above the peptidyl transferase center, with an extended loop that inserts deeply into the peptide exit tunnel. Intriguingly, distinct adenosine derivatives occupy the ligand-binding pocket of the CBS protein in different structural states of the 50S subunit. Molecular dynamics simulations indicate that ATP binding induces a more contracted conformation of the extended loop, suggesting that nucleotide occupancy may modulate this protein’s ribosome-association mode. Biochemical and bioinformatic analyses reveal that the extended loop is predominantly found in archaea, suggesting lineage-specific adaptations of ribosome-associated CBS proteins. Furthermore, the relatively sparse and dispersed distribution of rRNA modifications likely reflects organism-specific adaptations. Collectively, this work provides a structural framework for understanding how CBS-family proteins engage the archaeal ribosome and how their association may be tuned by cellular nucleotide status, offering insights into the molecular diversity of ribosome-associated factors and their roles in stress adaptation.
Endothelial dysfunction and inflammation are pivotal contributors to pathological cardiac remodeling and its progression toward heart failure (HF). Sphingosine-1-phosphate receptor 3 (S1PR3), a G protein-coupled receptor enriched in endothelial cells (ECs), is an important regulator of endothelial function, but its role in pressure overload-induced cardiac remodeling remains unclear. In this study, we observed a substantial reduction in S1PR3 levels in cardiac ECs following transverse aortic constriction (TAC). Endothelial-targeted S1PR3 knockdown aggravated TAC-induced cardiac remodeling, as evidenced by aggravated myocardial fibrosis, cardiac hypertrophy, microvascular rarefaction, and inflammatory cell infiltration. Mechanistically, both in vitro and in vivo analyses showed that S1PR3 deficiency promoted endothelial inflammatory activation and NF-κB-associated signaling, and altered endothelial paracrine communication with cardiac fibroblasts and cardiomyocytes, thereby contributing to fibroblast activation and cardiomyocyte hypertrophy under pathological stress. Conversely, endothelial S1PR3 overexpression alleviated TAC-induced cardiac remodeling. Importantly, pharmacological activation of S1PR3 with CYM-5541 also attenuated functional impairment, reduced fibrosis and hypertrophy, preserved myocardial microvascular density, and suppressed inflammatory responses after TAC. Collectively, our findings identify endothelial S1PR3 as a protective regulator in pressure overload-induced cardiac remodeling and support S1PR3 as a potential therapeutic target for limiting maladaptive cardiac remodeling.
